N-substituted benzothiophenesulfonamide derivatives

ABSTRACT

The present invention relates to an N-substituted benzothiophenesulfonamide derivative or a pharmaceutically acceptable salt thereof and applications thereof. Furthermore, it provides an agent for preventing or treating cardiac or circulatory disease and so on caused by abnormal increase of production of angiotensin II or endothelin I based on chymase activity, or by activation of mast cell, and an agent for preventing adhesion after surgery, wherein the agent has a selective inhibitory action on chymase.

This application is a divisional of U.S. patent application Ser. No.10/388,378, filed Mar. 13, 2003, which is a continuation-in-part ofInternational Patent Application No. PCT/JP01/08061, filed Sep. 17,2001. The International Application claims priority of Japanese PatentApplication No. 2000-282046, filed Sep. 18, 2000, and claims priority ofJapanese Patent Application No. 2001-122972, filed Apr. 20, 2001. TheInternational Application was published in Japanese on Mar. 21, 2002, asWO 02/22595 A1 under PCT Article 21(2). This application also claimspriority to Japanese Application No. 2002-072305, filed Mar. 15, 2002,Japanese Application No. 2002-072306, filed Mar. 15, 2002, and JapaneseApplication No. 2002-072307, filed Mar. 15, 2002. Each of these priorapplications is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to medicaments, especially N-substitutedbenzothiophenesulfonamide derivatives or salts thereof which selectivelyinhibit chymase, and chymase inhibitors containing the same as theactive ingredient. Since the compounds have a selective inhibitoryaction on chymase, they are useful as agents for preventing or treatinghypertension, hypercardia, cardiac infarction, arteriosclerosis,diabetic or non-diabetic renal diseases, diabetic retinopathy,restenosis after percutaneous transluminal coronary angioplasty(hereinafter, abbreviated as PTCA), intimal thickening after bypassgrafting, chronic rheumatism, keloid, psoriasis, allergy, inflammation,asthma, atopic dermatitis, solid tumors and pulmonary hypertensioncaused by abnormal increase of production of angiotensin II(hereinafter, abbreviated as Ang II) or endothelin I (hereinafter,abbreviated as ET-1) based on chymase-activity, or by activation of mastcell. In addition, the compounds of the invention are also useful asagents for preventing postoperative adhesion.

BACKGROUND OF THE INVENTION

Since Ang II and ET-1 have a cell growth-accelerating action in additionto a blood pressure-elevating action, they are considered as causativeagents or risk factors for diseases such as hypertension, hypercardia,cardiac infarction, arteriosclerosis, diabetic or non-diabetic renaldiseases and restenosis after PTCA. Moreover, it is known that Ang II isformed from angiotensin I (hereinafter, abbreviated as Ang I) byangiotensin converting enzyme (hereinafter, abbreviated as ACE), and alarge number of ACE inhibitors have been developed as agents forpreventing or treating the above diseases. On the other hand, it isknown that ET-1 is a physiologically active peptide composed of 21 aminoacid residues (hereinafter, abbreviated as ET(1-21)) which is formedfrom big endothelin (hereinafter, abbreviated as Big ET-1) by endothelinconverting enzyme (hereinafter, abbreviated as ECE), but ECE inhibitorsand ET-1 receptor antagonists are still in developmental stages asmedicaments.

Recently, in addition to ACE, an enzyme producing Ang. II from Ang I hasbeen discovered and named chymase. Urata et al. purified chymase fromhuman heart and has shown that 70 to 80% amount of Ang II produced inheart and blood vessels was due to chymase (J. Biol. Chem., 265, 22348(1990). Moreover, when the fact that no effectiveness of ACE inhibitorson restenosis after PTCA is observed [MERCAPTOR, study (Circulation, 86(1), 100 (1992)) and MARCAPTOR study (J. Am. Coll. Cardiol., 27(1), p. 1(1996))] and the fact that chymase inhibitors are effective on a canineintimal thickening model of grafted blood vessel using jugular vein(Miyazaki, Takai et al.; Febs. Lett., 467, 141 (2000)) are togetherconsidered, it is important to inhibit chymase rather than ACE forpreventing and treating cardiac and circulatory diseases and the likecaused by abnormal increase of the production of Ang II, and thus theapplication of chymase inhibitors to cardiac and circulatory diseases issuggested.

Furthermore, in the recent past, it has been revealed that chymasespecifically degrades Big ET-1 into a physiologically active peptidecomposed of 31 amino acid residues (hereinafter, abbreviated asET(1-31)). It has been reported that the ET(1-31) acts on the receptoron which original ET(1-21) acts, to cause bronchoconstriction andvasoconstriction (Kido et al.; J. Immunol., 159, 1987 (1997)). In thisconnection, with regard to the concentration in human blood, both ofET(1-31) and ET(1-21) have about the same distribution and activity, andafter cardiac infarction, ET(1-31) increases more largely than ET(1-21)does, which is maintained for two weeks after the incidence (Tamaki,Nishistu et al.; Jpn. J. Pharmacol., 82(suppl I), 26 (2000)), and thefact suggests importance of inhibition of chymase and application ofchymase inhibitors to cardiac and circulatory diseases.

Accordingly, chymase is considered to participate in production anddegradation of physiologically active peptides, remodeling ofextracellular matrix, network with cytokine, immunity, and the like andcontribute to restoration of metabolic turnover. Thus, a chymaseinhibitor is expected to apply to cardiac and circulatory diseases.

Moreover, as a result of administration of Ang II into a sponge in ahamster subdermally sponge-implanted model, removal of the sponge after7 days, and measurement of hemoglobin content, vascularization wasobserved (mainly capillary vessels). When ovalbumin (10 μg/site/day) asan antigen is administered to a sensitized animal via sponge,vascularization occurs as in the case of Compound 48/80. Thisvascularization was also inhibited by chymostatin (Muramatsu et al.; J.Biol. Chem., 275(8), 5545 (2000)). The above results indicate thatactivation of mast cells by antigen stimulation can also causevascularization, and chymase may be involved in this process. Thus, newroles of chymase are suggested in a variety of inflammatory allergydiseases. From such a viewpoint, a chymase inhibitor is expected toexhibit effects on solid tumors, diabetic retinopathy, rheumatoidarthritis and atherosclerosis.

Currently, as inhibitors against chymase, peptide-type chymaseinhibitors are disclosed in JP-A-1D-7661, JP-A-11-49739, JP-A-11-246437,WO98/09949, WO98/18794, WO99/45928, WO99/32459 and WO00/06594. On theother hand, non-peptide-type chymase inhibitors are disclosed inJP-A-10-8749-3, JP-A-10-245384, JP-A-12-95770, WO96/04248, WO97/11941,WO99/09977, WO00/03997, WO00/05204, WO00/10982, WO00/32587, WO01/32214,WO01/32621 and WO01/83471. However, until now, no clinically applicablechymase inhibitor has been found. Accordingly, it is desired to developa clinically applicable, chymase inhibitor which enables prevention andtreatment of cardiac and circulatory diseases and the like caused byabnormal increase of production of Ang II and ET-1, or by activation ofmast cell.

Pulmonary hypertension as above is a pathological condition in which theaverage blood pressure of pulmonary artery is increased (25 mmHg ormore) at rest through elevation of pulmonary vascular resistance andwhich may result in an after effect of hemodynamic change which is apossible danger to life. Slight physical exertion develops symptoms suchas shortness of breath breathing difficulty, fatigue, spasm of vertigoand loss of consciousness. In particular, pulmonary hypertension whosecause is unknown is called primary pulmonary hypertension, which breaksout with a frequency of 1 to 3 persons per 1 million persons and is adisease of a very bad prognosis, average survival time being 3 to 5years from its diagnosis.

As a treatment for pulmonary hypertension, a therapy of constantintravenous infusion of a prostacyclin injection is introduced and showsa therapeutic effect (N. Engl. J. Med., 334, 296 (1996)). However, sincea drug solution is constantly infused in this therapy, it is necessaryto indwell a central venous catheter and carry a pump and hence thetherapy imposes a heavy burden on patients and troubles such asinfection at a catheter inserted part may sometimes occur. Moreover, atherapy of inhalation of nitrogen monoxide (NO) is effective forselective pulmonary vasodilation and is an indispensable therapy at thetreatment of pulmonary hypertension in intensive care field, but thetherapy requires a large-scale exclusive instrument as well as there area lot of points to be improved in view of safety management (NihonRinsho, 59, 1126 (2001)).

In addition, application to pulmonary hypertension is investigated usinga pharmaceutical agent such as an endothelin receptor blocker, aphosphodiesterase inhibitor, a thromboxane synthesis inhibitor or anangiotensin II receptor blocker. However, these agents are not usedclinically because they exhibit insufficient effect or adverse effectfor example, most of them cause systemic blood-pressure decrease (NihonRinsho, 59, 1139 (2001)).

There is a report that chymase-containing mast cells are accumulated inthe lung tissue and pulmonary artery of pulmonary hypertension patients(Am. J. Respir. Crit. Care. Med., 160, 1303 (1999), Thorax., 54, 88(1999)), and chymase released from the mast cells accumulated in thelung is considered to be one cause of thickening of vascular tunicamedia. Moreover, there is a suggestion that an acylsulfonamidederivative which is a chymase inhibitor may be an agent for treating orpreventing pulmonary hypertension (JP-A-2001-97946). However, there isno report that a specific chymase inhibitor is actually effective forpreventing or treating pulmonary hypertension.

Furthermore, a tissue adhesion in the body of mammals including humanoccurs after surgery in clinical fields such as gastroenterology,cardiology, orthopedics, gynecology and ophthalmology and exerts astrong influence on prognosis together with pain in patients. Forexample, in the case of abdominal operation, there arises a phenomenonthat intraperitoneal organs such as abdominal wall and intestinal tractsmutually adhere after the operation, which sometimes causes ileus. Insome cases, re-operation is required. In gynecological field,postoperative adhesion occurs in the patients who had an infectionoperation or intrapelvic operation, and sometimes causes sterilitythrough tubal blockage. Also in cardiosurgery field, there is a casethat re-operation is restricted by adhesion or there is a possibleproblem of bleeding at re-operation. In ophthalmic region, it becomesdifficult to maintain quality of vision including insufficient controlof intraocular pressure when organic adhesion or postoperative adhesionoccurs.

As a prevention of postoperative adhesion, there are attempts to employa variety of pharmaceutical agents or special films. As thepharmaceutical agents for preventing adhesion, there may be mentionedhigh-molecular weight polysaccharides having a wound surface-coveringaction such as sodium alginate, sodium chondroitin sulfate,high-molecular weight dextran and sodium hyaluronate. As agents forpreventing postoperative adhesion of tubal orthosis, glucocorticoidssuch as dexamethasone and triamcinolone acetonide are employed. Asfilms, films or sponges using gelatin (Gelfilm, Gelfoam (registeredtrademarks)), polytetrafluoroethylene sheets (Gore-Tex (registeredtrademark)) and hyaluronic acid sheets modified with carboxymethylcellulose or the like (Seprafilm (registered trademark)) are employed.However, any agents are not satisfactory in view of the effects.

In this regard, recently, there are reported that a peptideSuc-Val-Pro-Phe^(P)(OPh)₂ which is a chymase inhibitor suppressesadhesion of organs after rubbing the uterus of a hamster adhesion model(Eur. J. Pharmacol., 435, 265 (2002)) and also adhesion at filteringblebs in a canine trabeculectomy model (Nihon Ganka gakkai Zasshi, Vol.106, (extra number), 131 (2002)). In addition, it is suggested that achymase inhibitor which is a quinazoline derivative can be utilized forpreventing postoperative adhesion through alleviation of extracellularmatrix dysbolism (WO01/62292).

DISCLOSURE OF THE INVENTION

As a result of the extensive studies for achieving the above objects,the present inventors have found that an N-substitutedbenzothiophenesulfonamide derivative or a pharmaceutically acceptablesalt thereof has an excellent and selective human chymase inhibitoryactivity and is stable even in rat blood plasma. The N-substitutedbenzothiophenesulfonamide derivative represented by formula (I) or apharmaceutically acceptable salt thereof according to the invention hasa strong inhibitory activity against chymase and is a extremely usefulcompound for preventing or treating cardiac or circulatory diseases andthe like caused by abnormal increase of production of Ang. II or ET-1based on chymase activity, or by activation of mast cell.

The N-substituted benzothiophenesulfonamide derivative represented byformula (I) or a pharmaceutically acceptable salt thereof according tothe invention is useful as an agent for preventing or treating pulmonaryhypertension and as an agent for preventing adhesion.

Also, it has been found that compounds represented by formulae

have a strong inhibitory activity against chymase and are extremelyuseful for preventing or treating cardiac or circulatory diseases andthe like caused by abnormal increase of production of Ang II or ET-1, orby activation of mast cell based on chymase activity.

Namely, the invention relates to an N-substitutedbenzothiophenesulfonamide derivative represented by formula (I):

wherein R¹ represents a hydrogen atom, a halogen atom or a lower alkylgroup;

-   R² represents a lower alkyl group;-   R³ and R⁴ each may be the same or different and represents a    hydrogen atom, a lower alkoxycarbonyl group, a lower alkylsulfonyl    group, a benzoyl group, an acyl group having 1 to 4 carbon atoms, a    lower alkoxy group, a lower alkoxycarbonylmethylthioacetyl group, a    nitro group, —CONHR⁶ in which R⁶ represents a hydrogen atom, a lower    alkoxycarbonylmethyl group, a carboxymethyl group or —CH(CH₂OH)COOR⁷    in which R⁷ represents a hydrogen atom or a lower alkyl group, a    group represented by formula:

in which R⁷ has the same meaning as above, a group represented byformula:

in which R⁸ and R⁹ each may be the same or different and represents ahydrogen atom, a lower alkyl group, a lower alkylsulfanyl group, a loweralkylsulfinyl group, a lower alkylsulfonyl group or a loweralkoxycarbonyl, group, a hydroxy lower alkyl group, cyano group or amonocyclic heterocyclic group represented by formulae:

in which A represents an oxygen atom, a sulfur atom or NH and the dottedpart represents a single bond or a double bond provided that thehydrogen atom on the ring may be replaced by a lower alkyl group whichmay be substituted by a halogen atom, a lower alkoxy group, a hydroxylower alkyl group, a lower alkoxycarbonyl group or a carboxyl group,provided that R³ and R⁴ are not hydrogen atoms at the same time; and

-   R⁵ represents a hydrogen atom, a lower alkoxy group or a lower alkyl    group, except the compounds represented by formulae

or a pharmaceutically acceptable salt thereof.

Moreover, the invention relates to the N-substitutedbenzothiophenesulfonamide derivative described above, wherein saidderivative or a pharmaceutically acceptable salt thereof is selectedfrom the group consisting of methyl4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylbenzoate,sodium methyl4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylbenzoate,isopropyl4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylbenzoate,N-(4-acetyl-2-methanesulfonylphenyl)-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,N-(4-benzoyl-2-methanesulfonylphenyl)-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,methyl4-(5-fluoro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylbenzoate,methyl4-(5-methyl-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylbenzoate,N-(4-acetyl-2-methanesulfonylphenyl)-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,methyl4-(3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylbenzoate,2-[4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylphenyl]oxazole-4-carboxylicacid,2-[4-(5-fluoro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylphenyl]oxazole-4-carboxylicacid, disodium2-[4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylphenyl]oxazole-4-carboxylate,disodium2-[4-(5-fluoro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylphenyl]oxazole-4-carboxylate,2-[4-(5-fluoro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylphenyl]thiazole-4-carboxylicacid,5-fluoro-N-[4-(4-hydroxymethylthiazol-2-yl)-2-methanesulfonylphenyl]-3-methylbenzo[b]thiophene-2-sulfonamide,5-fluoro-N-[2-methanesulfonyl-4-(5-methoxy-4-methyloxazol-2-yl)phenyl]-3-methylbenzo[b]thiophene-2-sulfonamide,5-fluoro-N-[2-methanesulfonyl-4-(5-methyloxazol-2-yl)phenyl]-3-methylbenzo[b]thiophene-2-sulfonamideand5-fluoro-N-[2-methanesulfonyl-4-((E)-2-methanesulfinyl-2-methylsulfanylvinyl)phenyl]-3-methylbenzo[b]thiophene-2-sulfonamide.

Furthermore, the invention relates to a pharmaceutical compositioncomprising an N-substituted benzothiophenesulfonamide derivativerepresented by formula (I):

wherein R¹ represents a hydrogen atom, a halogen atom or a lower alkylgroup;

-   R² represents a lower alkyl group;-   R³ and R⁴ each may be the same or different and represents a    hydrogen atom, a lower alkoxycarbonyl group, a lower alkylsulfonyl    group, a benzoyl group, an acyl group having 1 to 4 carbon atoms, a    lower alkoxy group, a lower alkoxycarbonylmethylthioacetyl group, a    nitro group, —CONHR⁶ in which R⁶ represents a hydrogen atom, a lower    alkoxycarbonylmethyl group, a carboxymethyl group or —CH(CH₂OH)COOR⁷    in which R represents a hydrogen atom or a lower alkyl group, a    group represented by formula:

in which R⁷ has the same meaning as above, a group represented byformula:

in which R⁸ and R⁹ each may be the same or different and represents ahydrogen atom, a lower alkyl group, a lower alkylsulfanyl group, a loweralkylsulfinyl group, a lower alkylsulfonyl group or a loweralkoxycarbonyl group, a hydroxy lower alkyl group, cyano group or amonocyclic heterocyclic group represented by formulae:

in which A represents an oxygen atom, a sulfur atom or NH and the dottedpart represents a single bond or a double bond provided that thehydrogen atom on the ring may be replacted by a lower alkyl group whichmay be substituted by a halogen atom, a lower alkoxy group, a hydroxylower alkyl group, a lower alkoxycarbonyl group or a carboxyl group,provided that R³ and R⁴ are not hydrogen atoms at the same time; and

-   R⁵ represents a hydrogen atom, a lower alkoxy group or a lower alkyl    group, or a pharmaceutically acceptable salt thereof.

Still further, the invention relates to a chymase inhibitor comprisingthe N-substituted benzothiophenesulfonamide derivative or a salt thereofdescribed above.

Moreover, the invention relates to an agent for preventing or treatinghypertension, hypercardia, cardiac failure, cardiac infarction,arteriosclerosis, diabetic or non-diabetic renal disease, diabeticretinopathy, ischemic re-perfusion disorder, restenosis after PCTA,intimal thickening after bypass grafting, chronic rheumatism, keloid,psoriasis, allergy, inflammation, asthma, atopic dermatitis, solidtumors, pulmonary hypertension, wherein the agent comprises theN-substituted benzothiophenesulfonamide derivative or a pharmaceuticallyacceptable salt thereof described above.

Furthermore, the invention relates to an agent for preventing adhesioncomprising the N-substituted benzothiophenesulfonamide derivative or apharmaceutically acceptable salt thereof described above.

BEST MODE FOR CARRYING OUT THE INVENTION

Examples of the halogen atom for R¹ include a fluorine atom, a chlorlineatom, a bromine atom or an iodine atom, and particularly, a fluorineatom or a chlorine atom is preferable.

Examples of the lower alkyl group for R¹, R², R⁵, R⁷, R⁸ and R⁹ includea methyl group, an ethyl group, a propyl group, an isopropyl group, abutyl group, an isobutyl group, a sec-butyl group or a tert-butyl group,and particularly, a methyl group or an ethyl group is preferable.

Examples of the lower alkoxycarbonyl group for R³, R⁴, R⁸ and R⁹ includea methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonylgroup, an isopropoxycarbonyl group, a butoxycarbonyl group, anisobutoxycarbonyl group, a sec-butoxycarbonyl group or atert-butoxycarbonyl group, and particularly, a methoxycarbonyl group, anethoxycarbonyl group, an isopropoxycarbonyl group or atert-butoxycarbonyl group is preferable.

Examples of the lower alkylsulfonyl group for R³, R⁴, R⁸ and R⁹ includea methanesulfonyl group, an ethanesulfonyl group, a propanesulfonylgroup, an isopropanesulfonyl group, a butanesulfonyl group, anisobutanesulfonyl group, a sec-butanesulfonyl group or atert-butanesulfonyl group, and particularly, a methanesulfonyl group oran ethanesulfonyl group is preferable.

Examples of the acyl group having 1 to 4 carbon atoms for R³ and R⁴include a formyl group, an acetyl group, a propionyl group, a butyrylgroup or an isobutyryl group, and particularly, an acetyl group ispreferable.

Examples of the lower alkoxy group for R³, R⁴ and R⁵ include a methoxygroup, an ethoxy group, a propoxy group, an isopropoxy group, a butoxygroup, an isobutoxy group, a sec-butoxy group or a tert-butoxy group,and particularly, a methoxy group or an ethoxy group is preferable.

Examples of the lower alkoxycarbonylmethylthioacetyl group for R³ and R⁴include a methoxycarbonylmethylthioacetyl group, anethoxycarbonylmethylthioacetyl group, a propoxycarbonylmethylthioacetylgroup, an isopropoxycarbonylmethylthioacetyl group, abutoxycarbonylmethylthioacetyl group, anisobutoxycarbonylmethylthioacetyl group, asec-butoxycarbonylmethylthioacetyl group or atert-butoxycarbonylmethylthioacetyl group, and particularly, amethoxycarbonylmethylthioacetyl group or anethoxycarbonylmethylthioacetyl group is preferable.

In the case that R³ and R⁴ each is —CONHR⁶, examples of the loweralkoxycarbonylmethyl group for R⁶ include a methoxycarbonylmethyl group,an ethoxycarbonylmethyl group, a propoxycarbonylmethyl group, anisopropoxycarbonylmethyl group, a butoxycarbonylmethyl group, anisobutoxycarbonylmethyl group, a sec-butoxycarbonylmethyl group or atert-butoxycarbonylmethyl group, and particularly, amethoxycarbonylmethyl group or an ethoxycarbonylethyl group, or anisopropoxycarbonylmethyl group is preferable

Examples of the hydroxy lower alkyl group for R³ and R⁴ include a linearor branched hydroxy lower alkyl group having 1 to 4 carbon atoms such asa hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group or ahydroxybutyl group, and particularly a hydroxymethyl group or ahydroxyethyl group is preferable.

Examples of the lower alkylsulfanyl group for R⁸ and R⁹ include a linearor branched lower alkylsulfanyl group having 1 to 4 carbon atoms such asa methylsulfanyl group, an ethylsulfanyl group, a propylsulfanyl groupor a butylsulfanyl group, and particularly, a methylsulfanyl group or anethylsulfanyl group.

Examples of the lower alkylsulfinyl group for R⁸ and R⁹ include a linearor branched lower alkylsulfinyl group having 1 to 4 carbon atoms such asa methanesulfinyl group, an ethanesulfinyl group, a propanesulfinylgroup or a butanesulfinyl group, and particularly, a methanesulfinylgroup or an ethanesulfinyl group is preferable.

As the group represented by the formula:

for example, a vinyl group, a methylsulfanylvinyl group,methanesulfinylvinyl group or 2-methanesulfinyl-2-methylsulfanylvinylgroup is preferable.

The meanings of the lower alkoxy group, the hydroxy lower alkyl groupand the lower alkoxycarbonyl group by which the hydrogen atom on thering represented by the formulae:

may be replaced are as mentioned in the above. Moreover, the lower alkylgroup which may be substituted by a halogen atom means a lower alkylgroup substituted by a fluorine atom, a chlorine atom, a bromine atom oran iodine atom in addition to the above-described lower alkyl group.Examples thereof include a chloromethyl group, a bromomethyl group, adichloromethyl group or 1-chloroethyl group

One or two of the lower alkyl groups which may be substituted by ahalogen atom, lower alkoxy-groups, hydroxy lower alkyl groups, loweralkoxycarbonyl groups or carboxyl groups may be present assubstituent(s) on each heterocycle and the substituents may be the sameor different.

Examples of the monocyclic heterocylic group represented by theformulae:

in which A represents an oxygen atom, a sulfur atom or NH and the dottedpart represents a single bond or a double bond, include thoserepresented by the following formulae.

Specific examples of the monocyclic heterocylic group represented by theformulae:

in which A represents an oxygen atom, a sulfur atom or NH and the dottedpart represents a single bond or a double bond, as well as the hydrogenatom on the ring may be replaced by a lower alkyl group which may besubstituted by a halogen atom, a lower alkoxy group, a hydroxy loweralkyl group, a lower alkoxycarbonyl group or a carboxyl group,preferably include those represented by the formulae:

and these substituents are preferably substituted as R⁴. In this case,it is further preferable that R³ is a methanesulfonyl group and R⁵ is ahydrogen atom.

In this regard, examples of specific compounds include methyl4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylbenzoate,sodium methyl 4chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylbenzoate,isopropyl4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylbenzoate,N-(4-acetyl-2-methanesulfonylphenyl)-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,N-(4-benzoyl-2-methanesulfonylphenyl)-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,ethyl4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylbenzoate,tert-butyl4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylbenzoate,methyl4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylbenzoate,methyl4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-5-methanesulfonyl-2-methylbenzoate,dimethyl4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)isophthalate,methyl4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methoxybenzoate,methyl4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-nitrobenzoate,ethyl 4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino) benzoate,5-chloro-N-(2,4-dimethanesulfonylphenyl)-3-methylbenzo[b]thiophene-2-sulfonamide,N-(4-acetyl-2-nitrophenyl)-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,5-chloro-N-(4-hydroxymethyl-2-methanesulfonylphenyl)-3-methylbenzo[b]thiophene-2-sulfonamide,N-(4-benzoylphenyl)-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,chloro-N-(2-methanesulfonylphenyl)-3-methylbenzo[b]thiophene-2-sulfonamide,methyl4-(5-fluoro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylbenzoate,methyl4-(5-methyl-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylbenzoate,N-(4-acetyl-2-methanesulfonylphenyl)-5-fluoro-3-methylbenzo[b]thiophene-2-sulfonamide,methyl4-(3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylbenzoate,methyl2-[4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylphenyl]oxazole-4-carboxylate,methyl2-[4-(5-fluoro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylphenyl]oxazole-4-carboxylate,2-[4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylphenyl]oxazole-4-carboxylicacid,2-[4-(5-fluoro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylphenyl]oxazole-4-carboxylicacid, disodium2-[4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylphenyl]oxazole-4-carboxylate,disodium2-[4-(5-fluoro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylphenyl]oxazole-4-carboxylate,5-fluoro-N-(2-methanesulfonyl-4-oxazol-5-ylphenyl)-3-methylbenzo[b]thiophene-2-sulfonamide,2-[4-(5-fluoro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylphenyl]thiazole-4-carboxylicacid,methyl-2-[4-(5-fluoro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylphenyl]thiazole-4-carboxylate,5-fluoro-N-[4-(4-hydroxymethylthiazol-2-yl)-2-methanesulfonylphenyl]-3-methylbenzo[b]thiophene-2-sulfonamide,N-[4-(4-chloromethylthiazol-2-yl)-2-methanesulfonylphenyl]-5-fluoro-3-methylbenzo[b]thiophene-2-sulfonamide,5-fluoro-N-[2-methanesulfonyl-4-(4-methylthiazol-2-yl)phenyl]-3-methylbenzo[b]thiophene-2-sulfonamide,5-fluoro-N-[2-methanesulfonyl-4-(2-methylthiazol-4-yl)phenyl]-3-methylbenzo[b]thiophene-2-sulfonamide,5-fluoro-N-[2-methanesulfonyl-4-(5-methylthiazol-2-yl)phenyl]-3-methylbenzo[b]-thiophene-2-sulfonamide,5-fluoro-N-[2-methanesulfonyl-4-(5-methoxy-4-methylthiazol-2-yl)phenyl]-3-methylbenzo[b]thiophene-2-sulfonamide,5-fluoro-N-[2-methanesulfonyl-4-(4,5-dimethylthiazol-2-yl)phenyl]-3-methylbenzo[b]thiophene-2-sulfonamide,5-fluoro-N-[4-(4-hydroxymethylexazol-2-yl)-2-methanesulfonylphenyl]-3-methylbenzo[b]thiophene-2-sulfonamide,N-[4-(4-chloromethyloxazol-2-yl)-2-methanesulfonylphenyl]-5-fluoro-3-methylbenzo[b]thiophene-2-sulfonamide,5-fluoro-N-[2-methanesulfonyl-4-(4-methyloxazol-2-yl)phenyl]-3-methylbenzo[b]thiophene-2-sulfonamide,5-fluoro-N-[2-methanesulfonyl-4-(5-methoxy-4-methyloxazol-2-yl)phenyl]-3-methylbenzo[b]thiophene-2-sulfonamide,5-fluoro-N-[2-methanesulfonyl-4-(5-ethoxy-4-methyloxazol-2-yl)phenyl]-3-methylbenzo[b]thiophene-2-sulfonamide,5-fluoro-N-[2-methanesulfonyl-4-(4,5-dimethyloxazol-2-yl)phenyl]-3-methylbenzo[b]thiophene-2-sulfonamide,5-fluoro-N-[2-methanesulfonyl-4-(5-methyloxazol-2-yl)phenyl]-3-methylbenzo[b]thiophene-2-sulfonamide and5-fluoro-N-[2-methanesulfonyl-4-((E)-2-methanesulfinyl-2-methylsulfanyl-vinyl)phenyl]-3-methylbenzo[b]thiophene-2-sulfonamide.

Of the above-described compounds, methyl4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylbenzoate,sodium methyl4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylbenzoate,isopropyl4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylbenzoate,N-(4-acetyl-2-methanesulfonylphenyl)-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,N-(4-benzoyl-2-methanesulfonylphenyl)-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,methyl4-(5-fluoro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylbenzoate,methyl4-(5-methyl-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylbenzoate,N-(4-acetyl-2-methanesulfonylphenyl)-5-fluoro-3-methylbenzo[b]thiophene-2-sulfonamide,methyl4-(3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylbenzoate,2-[4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylphenyl]oxazole-4-carboxylicacid,2-[4-(5-fluoro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylphenyl]oxazole-4-carboxylicacid, disodium2-[4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylphenyl]oxazole-4-carboxylate,disodium2-[4-(5-fluoro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylphenyl]oxazole-4-carboxylate,2-[4-(5-fluoro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylphenyl]thiazole-4-carboxylicacid,5-fluoro-N-[4-(4-hydroxymethylthiazol-2-yl)-2-methanesulfonylphenyl]-3-methylbenzo[b]thiophene-2-sulfonamide,5-fluoro-N-[2-methanesulfonyl-4-(5-methoxy-4-methyloxazol-2-yl)phenyl]-3-methylbenzo[b]thiophene-2-sulfonamide,5-fluoro-N-[2-methanesulfonyl-4-(5-methyloxazol-2-yl)phenyl]-3-methylbenzo[b]thiophene-2-sulfonamideand5-fluoro-N-[2-methanesulfonyl-4-((E)-2-methanesulfinyl-2-methylsulfanylvinyl)phenyl]-3-methylbenzo[b]thiophene-2-sulfonamideare preferable.

The following will describe the process for producing the N-substitutedbenzothiophenesulfonamide derivative or a salt thereof of the invention.The compound of the general formula (I) of the invention can be producedthrough the production process illustrated by the following reactionscheme.

That is, the compound can be produced by reacting an amine representedby the compound (III) with an sulfonyl chloride (II) in the presence ofa base such as sodium amide, lithium amide, sodium hydride, potassiumcarbonate, potassium tert-butoxide, triethylamine,ethyldiisopropylamine, pyridine, or 1,8-diazabicyclo[5.4.0]undec-7-ene(hereinafter, abbreviated as DBU) in a solvent such as dioxane,tetrahydrofuran (hereinafter, abbreviated as THF), acetone,dimethylformamide (hereinafter, abbreviated as DMF), dimethyl sulfoxide(hereinafter, abbreviated as DMSO), chloroform, pyridine or a mixedsolvent thereof within the range of −10° C. to a boiling point of thesolvent.

In this connection, in the case of the compound of the general formula(I) wherein R³ is a lower alkylsulfonyl group, R⁵ is a hydrogen atom,and R⁴ is a group represented by the general formula:

in which A has the same meaning as in the general formula (I) and R¹⁰and R¹¹ each may be the same or different and represents a hydrogenatom, a lower alkyl group which may be substituted by a halogen atom, alower alkoxy group, a hydroxy lower alkyl group, a lower alkoxycarbonylgroup or a carboxyl group, the compound can be also produced by thefollowing production process.

In this case, the compound of the general formula (I) wherein R¹¹ is asubstituent other than a hydrogen atom can be also produced through theproduction process illustrated by the following reaction scheme.

That is, the compound (V) wherein R¹² and R¹³ represents a lower alkylgroup, is obtained by reacting an amine represented by the compound (IV)synthesized from 4-chlorobenzoic acid according to the method known in aliterature (J. Med. Chem., 40, 2017 (1997)), with an sulfonyl chloride(II) in the presence of a base such as sodium amide, lithium amide,sodium hydride, potassium carbonate, potassium tert-butoxide,triethylamine, ethyldiisopropylamine, pyridine or DBU in a solvent suchas dioxane, THF, acetone, DMF, DMSO, chloroform, pyridine or a mixedthereof within the range of −10° C. to a boiling point of the solvent(Step B), and then ester hydrolysis was carried out to obtain a compound(VI) (Step C). Thereafter, the compound (VIII) wherein R¹⁴ represents ahydrogen atom or a lower alkyl group and R¹⁵ represents a lower alkylgroup or a lower alkoxy group, is obtained by reacting the compound (VI)with an amine represented by the general formula (VII) in the presenceof a base such as triethylamine, ethyldiisopropylamine or DBU using acondensing agent such as N,N′-dicyclohexylcarbodiimide (hereinafter,abbreviated as DCC) or 1-ethyl-3-(3-dimethylaminopropylcarbodiimide(hereinafter, abbreviated as EDC) (Step D), and then a compound (Ia) isobtained by using phosphorus oxychloride or diphosphorus pentasulfide(Step E), whereby the production is completed.

Furthermore, in the case of the compound wherein R¹¹ is a hydrogen atom,the compound of the general formula (I) can be also produced through theproduction process illustrated by the following reaction scheme.

That is, a compound (Ib) is obtained in accordance with the method knownin literatures (Tetrahedron Letters, 33, 907 (1992), J. Org. Chem., 38,26 (1973), J. Org. Chem., 58, 4494 (1993), Org. Lett., 2, 1165 (2000),tetrahedron-Letters, 42, 4171 (2001)) starting with a compound (IX)wherein R¹⁶ represents a hydroxymethyl group or a mercaptomethyl groupwhich may have a protective group such as a trityl group and R¹⁷represents a lower alkyl group (Steps F and G). The compound (IX) isobtained by reacting the compound (VI) with serine ester hydrochloride,cysteine ester hydrochloride, S-tritylcysteine ester or the like in thepresence of a base such as triethylamine, ethyldiisopropylamine or DBUusing a condensing agent such as EDC. A compound (Ic) can be produced byfurther converting the ester group into a hydroxymethyl group throughreduction (Step H). Also, a compound (Id) wherein R¹⁸ represents ahalogen atom cab be produced by halogenating the compound (Ic) (Step I),and a compound (Ie) can be further produced by reducing the halogen atomof the compound (Id) to form a methyl group (Step J).

In this connection, a compound (If) can be produced by subjecting thecompound (Ib) to ester hydrolysis (Step K).

Also, in the case of the compound of the general formula (I) wherein R³is a lower alkylsulfonyl group, R⁵ is a hydrogen atom, and R⁴ is a grouprepresented by the formula:

in which R¹⁹ and R²⁰ each may be the same or different and represents ahydrogen atom, a lower alkyl group, which may be substituted by ahalogen atom, a lower alkoxy group, a hydroxy lower alkyl group, a loweralkoxycarbonyl group or a carboxyl group, the compound of formula (I)can be also produced through the following production processillustrated by the following reaction scheme.

That is, a compound (XII) wherein R represents a halogen atom isobtained from the compound (XI) wherein R¹² has the same meaning asabove in accordance with the method known in a literature(JP-A-2000-256262) (Step L). Further, a compound (Ig) can be produced bysubjecting the compound (XII) to ring closure with thioacetamide orformamide (Step M).

In this connection, in the case of the compound of formula (I) whereinR³ is a lower alkylsulfonyl group, R⁵ is a hydrogen atom, and R⁴ is agroup represented by the formula:

the compound can be also produced through the following productionprocess illustrated by the following reaction scheme.

That is, a compound (XIV) is obtained by reducing the ester group of thecompound (V) wherein R¹² has the same meaning as above, followed byoxidation to form an aldehyde group (Steps N and O) and then a compound(Ih) can be produced in accordance with the method known in a literature(Bull. Chem. Soc. Jpn., 52, 2013 (1979)) (Step P).

The thus formed compound of formula (I) can be isolated and purified byconventional methods such as recrystallization and columnchromatography.

The compound of formula (I) of the invention can be formed into apharmaceutically acceptable salt with an acid or base, e.g., a salt withan inorganic acid such as hydrochloride, hydrobromide, hydroiodide,sulfate, nitrate or phosphate; a salt with an organic acid such asacetate, trifluoroacetate, oxalate, fumarate, maleate, tartrate,mesylate or tosylate; a salt with an alkali metal such as sodium salt orpotassium salt; or a salt with an alkaline earth metal such as calciumsalt depending on the compound, by a usual method.

The compound of formula (I) sometimes includes optical isomers based onan asymmetric carbon atom. These various types of isomers isolated andmixtures of these isomers are also encompassed within the invention.Moreover, the compound of formula (I) of the invention includes hydratesand various solvates. All the crystal forms are also encompassed withinthe compound of formula (I).

The invention also includes a medicament containing the N-substitutedbenzothiophenesulfonamide derivative represented by the above formula(I) or a pharmaceutically acceptable salt thereof. The medicamentincludes an agent for inhibiting chymase activity.

The medicament is effective for diagnosing, preventing and/or treatingdiseases caused by abnormal increase of production of angiotensin II orendothelin I, or by activation of mast cell.

The above-described diseases include circulatory diseases andinflammatory allergosis, and the like.

Specifically, the diseases include hypertension, hypercardia, cardiacfailure, cardiac infarction, arteriosclerosis, diabetic or non-diabeticrenal disease, diabetic retinopathy, ischemic re-perfusion disorder,restenosis after PTCA, intimal thickening after bypass grafting, chronicrheumatism, keloid, psoriasis, allergy, inflammation, asthma, atopicdermatitis, solid tumors, pulmonary hypertension, and the like.

Moreover, the medicament is effective for preventing a tissue adhesionafter surgery in clinical fields such as gastroenterology, cardiology,orthopedics, gynecology and ophthalmology.

The compound of formula (I) or a pharmaceutically acceptable saltthereof may be administered orally or parenterally. For theadministration, pharmaceutically acceptable additives such as anexcipient, a binder, a buffering agent, a thickener, a stabilizer, anemulsifier, a dispersing agent, a suspending agent, a preservative, andthe like may be incorporated and preparations can be formulated in ausual manner.

Examples of preparations for oral administration include tabletsincluding sugar-coated tablets and film-coated tablets, pills, granules,powders, capsules including soft capsules, liquids, syrups, emulsions,suspensions, and the like.

The preparations for oral administration can be manufactured with mixingadditives usually employed in the pharmaceutical field in accordancewith a known method. Examples of such additives include an excipientsuch as lactose, mannitol or anhydrous calcium hydrogen phosphate; abinder such as hydroxypropyl cellulose, methyl cellulose orpolyvinylpyrrolidone; a disintegrator such as starch and carboxymethylcellulose; a lubricant such as magnesium stearate or talc; and the like.

Parenteral administration may be conducted as injections, preparationsfor rectal administration, preparations for topical administration, andthe like. The injections include aseptic solutions or suspensions. Theseinjections can be manufactured by dissolving or suspending the compoundof formula (I) or a pharmaceutically acceptable salt thereof in JapanesePharmacopoeia-grade water for injection, for example. As needed, anisotonic agent such as sodium chloride, a buffering agent such as sodiumdihydrogen phosphate or sodium monohydrogen phosphate, a solubilizingagent, or the like may be mixed. Moreover, the injections may bepreparation to be dissolved before use (powder-packed or freeze-dried),which can be manufactured in a usual manner with adding an excipientsuch as mannitol or lactose.

Suppositories may be mentioned as the preparations for rectaladministration. The suppositories are manufactured by dissolving orsuspending the compound of formula (I) or a pharmaceutically acceptablesalt thereof in a base material such as cacao butter or macrogol andmolding the mixture in a mold. Moreover, the preparations for rectaladministration may be manufactured by charging liquids or creams intocontainers for injection.

The preparations for topical application include liquids, eye-drops,creams, ointments, gel preparations, sprays, powders and the like. Theliquids can be manufactured by adding the compound of formula (I) or apharmaceutically acceptable salt thereof into water and further addingthereto a stabilizer, a solubilizer, a thickener, a dispersing agent, asuspending agent, and the like as needed. As the thickener, gelatin,sodium hyaluronate, high-molecular weight dextran, sodium alginate,sodium chondroitin sulfate or the like may be employed. The eye-dropscan be manufactured by adding a buffering agent, a pH adjusting agentand an isotonic agent as well as a preservative. The creams andointments can be manufactured using an aqueous or oily base material,e.g., water, liquid paraffin, a vegetable oil such as peanut oil orcastor oil, or macrogol. The gel preparations can be manufactured by aknown method using gelatin, pectin, carrageenan, agar, tragacanth, anarginate salt, a cellulose ether such as methyl cellulose or sodiumcarboxymethyl cellulose, a pectin derivative, a polyacrylate, apolymethacrylate, polyvinyl alcohol, polyvinyl pyrrolidone or the like.The sprays can be manufactured by dissolving or suspending the compoundof formula (I) or a pharmaceutically acceptable salt thereof in water orthe like and charging the mixture into spraying containers. In the caseof the powders, the compound of formula (I) or a pharmaceuticallyacceptable salt thereof may be used as it is or may be mixed with anappropriate excipient to manufacture the powders.

Moreover, the compound of formula (I) or a pharmaceutically acceptablesalt thereof can be administered after a gelatin sponge or a sheet ofhyaluronic acid or the like is impregnated or coated with its solution.

Furthermore, the compound of formula (I) or a pharmaceuticallyacceptable salt thereof may be administered intranasally or byinhalation. Preparations for inhalation have an advantage of attainingquick action since the preparations deliver the compound directly to thepulmonary area. In the case of aerosols, particle size of the aerosolsis preferably from 0.5 to 5 μm and the aerosols can be sprayedquantitatively using an appropriate propellant such as1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, carbondioxide, air or another suitable gas. These preparations may bemanufactured by a usual method, and a pH-adjusting agents such ascitrate, lactate or phosphate buffer; a stabilizer e.g., an antioxidantsuch as sodium hydrogen sulfite or tocopherol or a metal chelating agentsuch as ethylenediamine tetraacetic acid; a preservative such asbenzarconium chloride or a p-oxybenzoic acid ester; and the like may beadded, if necessary.

The dose of the compound of formula (I) or pharmaceutically acceptablesalt thereof per day for an adult is suitably from about 10 μg to 1 g,preferably about 100 μg to 100 mg in the case of oral administration. Inthe case of administering as injections, the dose may be from one tenthto a half of the dose in the case of oral administration. Moreover, inthe case of directly administering to an operated part, the dose may befrom 1 ng to 1 g. The dose can be appropriately changed depending on theconditions, body weight, age and the like of an individual patient.

The compound of formula (I) or a pharmaceutically acceptable saltthereof exhibits a low toxicity and no remarkable toxicity is observedthrough three days of observation after oral administration (singledose, 300 mg/kg) to 6-week-old male rats. Accordingly, these compoundsare judged to be highly safe.

EXAMPLES

The following will describe the invention in more detail with referenceto Examples and Test Examples, but the invention is not limited thereto.

Reference Example 1[4-(5-Fluoro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonyl]benzoicAcid

Into 500 mL of methanol was dissolved 24.8 g of methyl4-(5-fluoro-3-methylbenzo[b]-thiophene-2-sulfonylamino)-3-methanesulfonylbenzoate,and 50 mL of 1 mol/L sodium hydroxide was added thereto. After 3 hoursof stirring under heating and refluxing, the solvent was removed byevaporation under reduced pressure and water was added to the resultingresidue. The mixture was washed with ether. To the aqueous layer wasadded 2 mol/L hydrochloric acid, followed by extraction with ethylacetate. The organic layer was washed with saturated brine and thendried over anhydrous sodium sulfate. The solvent was removed byevaporation under reduced pressure and the resulting residue was washedwith ether to obtain 14.3 g of the title compound as colorless powder.

Melting point: 290° C.

¹H-NMR (CDCl₃):δ 2.66 (3H,s), 3.05 (3H,s), 6.76 (1H,dd,J=2.0,8.6 Hz),7.45 (1H,dd,J=2.0,8.6 Hz), 7.75 (1H,dd,J=4.6,9.0 Hz), 7.82 (1H,d,J=8.8Hz), 8.17 (1H,dd,J=2.0,8.8 Hz), 8.49 (1H,d,J=2.0 Hz),

IR ν_(max) (KBr):3239,2925,1687,1609,1501,1442,1421,1400,1356,1287,1161cm⁻¹.

Reference Example 2 Methyl(2S)-2-[4-(5-fluoro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylphenylcarboxyamido]propionate

Into 100 mL of dichloromethane was suspended 3.78 g of L-alanine methylester hydrochloride, and 3.8 mL of triethylamine was added at 0° C.Thereto was added 100 mL of dichloromethane suspension of 10.0 g of[4-(5-fluoro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonyl]benzoicacid. After 5 minutes of stirring at the same temperature, 5.19 g of EDChydrochloride was added and the mixture was stirred at room temperaturefor 19 hours. After the reaction was terminated with 1 mol/Lhydrochloric acid, the dichloromethane layer was separated. Afterremoval of the solvent by evaporation under reduced pressure, a mixedsolution of ethyl acetate-THF (1/1) was added to the resulting residue,followed by successive washing with water and saturated brine and dryingover anhydrous magnesium sulfate. The solvent was removed by evaporationunder reduced pressure and the resulting residue was washed withmethanol to obtain 9.22 g of the title compound as colorless powder.

Melting point: 162-163° C.

¹H-NMR (CDCl₃):δ 1.49 (3H,d,J=7.3 Hz), 2.69 (3H, s), 3.07 (3H,s), 3.79(3H,s), 4.74 (1H,dd,J=7.3,7.3 Hz), 6.96 (1H,d,J=7.3 Hz), 7.28(1H,ddd,J=2.4,8.6,8.8 Hz), 7.47 (1H,dd,J=2.4, 9.2 Hz), 7.77(1H,dd,J=4.7,8.8 Hz), 7.81 (1H,d,J=8.7 Hz), 7.89 (1H,dd,J=2.0,8.7 Hz),8.25 (1H,d,J=2.0 Hz), 9.71 (1H,s).

IR ν_(max)(KBr):3323,3222,3068,3003,2924,1737,1636,1607,1496,1306,1165,924 cm⁻¹.

methanesulfonylbenzoate, followed by addition of 170 mg of sodiumhydride (oily, 60%) at 0° C. After 20 minutes of stirring at the sametemperature, 1.28 g of5-chloro-2-chlorosulfonyl-3-methylbenzo[b]thiophene was added at 0° C.,followed by 1 hour of stirring at room temperature. Further, 150 mg ofsodium hydride (oily, 60%) was added at room temperature and the mixturewas stirred for 2 hours at the same temperature. After confirmation ofdisappearance of the starting material, the reaction was terminated byadding saturated aqueous ammonium chloride solution at 0° C., followedby extraction with ethyl acetate. The organic layer was washed withsaturated brine and then dried over anhydrous sodium sulfate. Thesolvent was removed by evaporation and the residue was purified bysilica gel column chromatography (ethyl acetate/hexane=3/1) to obtain911 mg of the title compound as colorless powder.

Melting point: 179-181° C.

¹H-NMR (CDCl₃):δ 2.70 (3H,s), 3.06 (3H,s), 3.90 (3H,s), 7.48(1H,dd,J=2.1,8.6 Hz), 7.74 (1H,d,J=8.6 Hz), 7.89 (1H,d,J-2.1 Hz), 7.86(1H,d,J=8.8 Hz), 8.19 (1H,dd,J=2.0,8.8 Hz), 8.50 (1H,d,J=2.0Hz), 9.84(1H,s).

IR ν_(max) (KBr):3217,1720,1608,1504,1442,1392,1308,1165,1119 cm⁻¹.

Example 2 Synthesis of ethyl4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylbenzoate(Compound 2)

In the same manner as in Example 1, 529 mg of the title compound wasobtained as colorless powder from 559 mg of ethyl4-amino-3-methanesulfonylbenzoate.

Melting point: 167-169° C.

¹H-NMR (CDCl₃):δ 1.36 (3H,t,J=7.1 Hz), 2.70 (3H,s), 3.06 (3H,s), 4.36(2H,q,J=7.1 Hz), 7.47 (1H,dd,J=2.0,8.8 Hz), 7.74 (1H,d,J=8.8 Hz), 7.78(1H,d,J=2.0 Hz), 7.86 (1H,d,J=8.8 Hz), 8.19 (1H,dd,J=2.0,8.8 Hz), 8.50(1H,d,J=2.0 Hz), 9.83 (1H,brs).

IR ν_(max) (KBr):3224,2985,1716,1608,1500,1358,1300,1142 cm⁻¹.

Example 3 Synthesis of tert-butyl4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylbenzoate(Compound 3)

In the same manner as in Example 1, 148 mg of the title compound wasobtained as colorless powder from 128 mg of tert-butyl4-amino-3-methanesulfonylbenzoate.

Melting point: 236-238° C.

¹H-NMR (CDCl₃):δ 1.54 (9H,s), 2.52 (3H,s), 3.28 (3H,s), 7.55-7.80(4H,m), 8.00 (1H,s), 8.25-8.30 (1H,m).

IR ν_(max) (KBr):3467,2974,2327,1705,1662,1597,1477,1396,1296,1130,1099cm⁻¹.

Example 4 Synthesis of Methyl4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-ethanesulfonylbenzoate(Compound 4)

In the same manner as in Example 1, 80 mg of the title compound wasobtained as colorless powder from 76 mg of methyl4-amino-3-ethanesulfonylbenzoate.

Melting point: 172-173° C.

¹H-NMR (CDCl₃):δ 1.27 (3H,t,J=7.3 Hz), 2.74 (3H,s), 3.24 (2H,q, J=7.3Hz), 3.77 (3H,s), 7.20-7.31 (2H,m), 7.43-7.56 (3H,m), 8.31 (1H,s).

IR ν_(max) (KBr):3482,3217,2931,1709,1597,1481,1439,1284,1126 cm⁻¹.

Example 5 Synthesis of methyl4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-5-methanesulfonyl-2-methylbenzoate(Compound 5)

Into 10 mL of THF was dissolved 135 mg of methyl4-amino-5-methanesulfonyl-2-methylbenzoate, followed by addition of 22mg of sodium hydride (oily, 60%) at room temperature. After 20 minutesof stirring at the same temperature, 130 mg of5-chloro-2-chlorosulfonyl-3-methylbenzo[b]thiophene was added at 0° C.,followed by 1 hour of stirring at room temperature and 5 hours ofheating under refluxing. Further, 1 mL of DMF, 22 mg of sodium hydride(oily, 60%) and 50 mg of5-chloro-2-chlorosulfonyl-3-methylbenzo[b]thiophene were added and themixture was heated under refluxing for 2.5 hours. After-confirmation ofdisappearance of the starting material, the reaction was terminated byadding saturated aqueous ammonium chloride solution at 0° C., followedby extraction with ethyl acetate. The organic layer was washed withsaturated brine and then dried over anhydrous sodium sulfate. Thesolvent was removed by evaporation and the residue was purified bysilica gel column chromatography (ethyl acetate/hexane=3/2) to obtain102 mg of the title compound as colorless powder.

Melting point: 205-207° C.

¹H-NMR (CDCl₃):δ 2.65 (3H,s), 2.71 (3H,s), 3.04 (3H,s), 3.87 (3H,s),7.49 (1H,dd,J=2.0,8.6 Hz), 7.68 (1H,s), 7.77 (1H,d,J=8.6 Hz), 7.80(1H,d,J=2.0 Hz), 8.42 (1H,s), 9.73 (1H,s).

IR ν_(max)(KBr):3259,1728,1604,1554,1504,1439,1385,1354,1300,1257,1157,1092 cm⁻¹.

Example 6 Synthesis of dimethyl4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)isophthalate(Compound 6)

Into 8 mL of THF was dissolved 115 mg of dimethyl 4-aminoisophthalate,followed by addition of 22 mg of sodium hydride (oily, 60%). After 20minutes of stirring at room temperature, 130 mg of5-chloro-2-chlorosulfonyl-3-methylbenzo[b]thiophene was added at thesame temperature, followed by 30 minutes of stirring at roomtemperature. Further, 26 mg of sodium hydride (oily, 60%) was added andthe whole was heated under refluxing for 6 hours. After confirmation ofdisappearance of the starting material, the reaction was terminated byadding saturated aqueous ammonium chloride solution at 0° C., followedby extraction with ethyl acetate. The organic layer was washed withsaturated brine and then dried over anhydrous sodium sulfate. Thesolvent was removed by evaporation and the residue was purified bysilica gel column chromatography (ethyl acetate/hexane=1/1) to obtain 62mg of the title compound as light yellow amorphous.

¹H-NMR (CDCl₃):δ 2.64 (3H,s), 3.88 (3H,s), 3.95 (3H,s), 7.44(1H,dd,J=2.0,8.8 Hz), 7.71 (1H,d,J=8.8 Hz), 7.74 (1H,d,J=2.0 Hz), 7.86(1H,d,J=8.8 Hz), 8.11 (1H,dd,J=2.0,8.8 Hz), 8.63 (1H,d,J=2.0 Hz).

IR ν_(max)(KBr):3440,3140,2954,1724,1693,1608,1500,1439,1331,1246,1165,1119 cm⁻¹.

Example 7 Synthesis of methyl4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methoxybenzoate(Compound 7)

Into 4 mL of pyridine were dissolved 120 mg of methyl4-amino-3-methoxybenzoate and 150 mg of5-chloro-2-chlorosulfonyl-3-methylbenzo[b]thiophene, followed by 14hours of stirring at room temperature. After confirmation ofdisappearance of the starting material, the reaction was terminated byadding water at 0° C., followed by extraction with ethyl acetate. Theorganic layer was washed with saturated brine and then dried overanhydrous sodium sulfate. The solvent was removed by evaporation andthen the residue was purified by silica gel column chromatography(chloroform/methanol=9/1) to obtain 110 mg of the title compound ascolorless amorphous.

¹H-NMR (CDCl₃):δ 2.55 (3H,s), 3.79 (3H,s), 3.86 (3H,s), 7.42(1H,dd,J=2.0,8.6 Hz), 7.45 (1H,dd,J=2.0,8.6 Hz), 7.61 (1H,d,J=2.0 Hz),7.62 (1H,d,J=8.6 Hz), 7.68 (1H,d,J=8.6 Hz), 7.71 (1H,d,J=2.0 Hz).

IR ν_(max) (KBr):3248,2951,1716,1601,1512,1439,1350,1284,1242,1161,1115cm⁻¹.

Example 8 Synthesis of methyl4-(5-chloro-3-methylbenzo-[b]thiophene-2-sulfonylamino)-3-nitrobenzoate(Compound 8)

In the same manner as in Example 6, 146 mg of the title compound wasobtained as yellow powder from 122 mg of methyl 4-amino-3-nitrobenzoate.

Melting point: 164-165° C.

¹H-NMR (CDCl₃):δ 2.47 (3H,s), 3.84 (3H,s), 7.56 (1H,d,J=8.6 Hz), 7.57(1H,brd,J=8.6 Hz), 8.01 (1H,d,J=1.8 Hz), 8.06 (1H,d,J=8.6 Hz), 8.07(1H,brd,J=8.6 Hz), 8.25 (1H,d,J=1.8 Hz).

IR ν_(max)(KBr):3442,3237,3060,2949,1732,1621,1535,1507,1440,1356,1297,1164,1106cm⁻¹.

Example 9 Synthesis of5-chloro-N-(2,4-dimethanesulfonylphenyl)-3-methylbenzo[b]thiophene-2-sulfonamide(Compound 9)

In the same manner as in Example 6, 368 mg of the title compound wasobtained as colorless powder from 200 mg of2,4-dimethanesulfonylaniline.

Melting point: 176-178° C.

¹H-NMR (DMSO-d₆):δ 2.65 (3H,s), 3.00 (3H,s), 3.07 (3H,s), 7.44(1H,dd,J=1.8,8.6 Hz), 7.71 (1H,d,J=8.6 Hz), 7.76 (1H,d,J=1.8 Hz), 7.92(1H,d,J=8.8 Hz), 8.04 (1H,dd,J=1.8,8.8 Hz), 8.34 (1H,d,J-1.8 Hz).

IR ν_(max) (KBr):3236,3020,1593,1489,1392,1354,1304,1157 cm⁻¹.

Example 10 Synthesis ofN-(4-acetyl-2-nitrophenyl)-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide(Compound 10)

In the same manner as in Example 6, 59 mg of the title compound wasobtained as colorless powder from 96 mg of 4 acetyl-2-nitroaniline.

Melting point: 130-131° C.

¹H-NMR (CDCl₃):δ 2.58 (3H,s), 2.69 (3H,s), 7.46 (1H,dd,J=2.0,8.6 Hz),7.73 (1H,d,J=8.6 Hz), 7.78 (1H,d,J=2.0 Hz), 8.05 (1H,d,J=8.8 Hz), 8.16(1H,dd,J=1.8,8.8 Hz), 8.74 (1H,d,J=1.8 Hz).

IR ν_(max)(KBr):3745,3479,3363,3262,3089,2927,2858,1689,1620,1531,1419,1354,1115,1080cm⁻¹.

Example 11 Synthesis ofN-(4-acetyl-2-methanesulfonylphenyl)-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide(Compound 11)

Into a mixed solvent of 20 mL of THF and 5 ml of DMF was dissolved 241mg of 4-amino-3-methanesulfonylacetophenone, followed by addition of 136mg of sodium hydride (oily, 60%) at −78° C. After 20 minutes of stirringat the same temperature, 350 mg of5-chloro-2-chlorosulfonyl-3-methylbenzo[b]thiophene was added at −78°C., and the mixture was gradually warmed and stirred at −10° C. for 1hour. After confirmation of disappearance of the starting material, thereaction was terminated by adding saturated aqueous ammonium chloridesolution at 0° C., followed by extraction with ethyl acetate. Theorganic layer was washed with saturated brine and then dried overanhydrous sodium sulfate. The solvent was removed by evaporation and theresidue was purified by silica gel column chromatography (ethylacetate/hexane=1/1) to obtain 427 mg of the title compound as colorlesspowder.

Melting point: 207-209° C.

¹H-NMR (CDCl₃):δ 2.56 (3H,s), 2.69 (3H,s), 3.07 (3H,s), 7.46(1H,dd,J=1.9,8.7 Hz), 7.72-7.79 (2H,m), 7.86 (1H,d,J=8.6 Hz), 8.10(1H,d,J=8.6 Hz), 8.40 (1H,d,J=1.9 Hz).

IR ν_(max)(KBr):3456,3236,3086,3005,2924,2854,1670,1593,1489,1389,1354,1308,1261,1165,1130,1053cm⁻¹.

Example 12 Synthesis ofN-(4-benzoyl-2-methanesulfonylphenyl)-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide(Compound 12)

In the same manner as in Example 11, 68 mg of the title compound wasobtained as colorless powder from 94 mg of4-amino-3-methanesulfonylbenzophenone.

Melting point: 144-146° C.

¹H-NMR (CDCl₃):δ 2.70 (3H,s), 3.08 (3H,s), 7.45-7.50 (3H,m), 7.58-7.62(2H,m), 7.68-7.71 (4H,m), 7.85 (1H,d,J=8.6 Hz), 7.97 (1H,d,J=8.6 Hz),8.31 (1H,brs).

IR ν_(max)(KBr):3456,3248,3001,2927,2858,2256,1709,1655,1597,1496,1450,1389,1350,1308,1161,1130,1084cm⁻¹.

Example 13 Synthesis of5-chloro-N-(4-hydroxymethyl-2-methanesulfonylphenyl)-3-methylbenzo[b]thiophene-2-sulfonamide(Compound 13)

Into 10 mL of toluene was dissolved 305 mg of Compound 1, and thesolution was cooled to −78° C., followed by addition of 2.2 mL of 1.01mol/L toluene solution of diisobutylaluminum hydride. After 20 minutesof stirring at the same temperature, the mixture was gradually warmed to0° C. and stirred for 1 hour. After the reaction was terminated byadding water, the mixture was diluted with ethyl acetate and saturatedaqueous potassium sodium tartrate solution were added, followed by 30minutes of stirring at room temperature. The mixture was extracted withethyl acetate and the organic layer was washed with saturated brine andthen dried over anhydrous sodium sulfate. The solvent was removed byevaporation and the residue was purified by silica gel columnchromatography (ethyl acetate/hexane=1/1) to obtain 230 mg of the titlecompound as colorless powder.

Melting point: 183-184° C.

¹H-NMR (CDCl₃):δ 1.83 (1H,brs), 2.69 (3H,s), 22.97 (3H-s), 4.69(2H,d,J=5.7 Hz), 7.47 (1H,dd,J=2.1,8.7 Hz), 7.57 (1H,dd,J=2.1,8.7 Hz),7.74 (1H,d,J=9.3 Hz), 7.78 (1H,d,J=9.3 Hz), 7.79 (1H,d,J=2.1 Hz), 7.86(1H,d,J=2.1 Hz), 9.49 (1H,brs).

IR ν_(max) (KBr):3563,3236,1612,1500,1392,1277,1142 cm^(−1.)

Example 14 Synthesis of ethyl4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)benzoate (Compound14)

Into 3 mL of pyridine was dissolved 60 mg of ethyl 4-aminobenzoate, and123 mg of 5-chloro-2-chlorosulfonyl-3-methylbenzo[b]thiophene was addedat 0° C., followed by 2 hours of stirring at room temperature. Afterconfirmation of disappearance of the starting material, 2 mol/Lhydrochloric acid was added, followed by extraction with ether. Theorganic layer was washed with saturated brine and then dried overanhydrous magnesium sulfate. The solvent was removed by evaporationunder reduced pressure and the resulting crude product was purified bysilica gel column chromatography (ethyl acetate/hexane=1/3) to obtain 80mg of the title compound as light pink powder.

Melting point: 224-226° C.

¹H-NMR (DMSO-d₆):δ 1.26 (3H,t,J=7.1 Hz), 2.50 (3H,s), 4.23 (2H,q,J=7.1Hz), 7.27 (2H,d,J=8.8 Hz), 7.57 (1H,dd,J=2.0,8.6 Hz), 7.84 (2H,d,J=8.8Hz), 8.01 (1H,d,J=2.0 Hz), 8.05 (1H,d,J=8.6 Hz).

IR ν_(max) (KBr):3213,1696,1608,1511,1347,1288,1159 cm⁻¹.

Example 15 Synthesis ofN-(4-benzoylphenyl)-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide(Compound 15)

In the same manner as in Example 14, 187 mg of the title compound wasobtained as colorless powder from 126 mg of 4-benzoylaniline.

Melting point: 198-200° C.

¹H-NMR (CDCl₃):δ 2.56 (3H,s), 7.22-7.26 (2H,m), 7.44-7.48 (3H,m),7.55-7.60 (1H,m), 7.70-7.76 (6H,m)

IR ν_(max) (KBr):3213,2927,1724,1639,1589,1508,1450,1408,1288,1234,1149cm⁻¹.

Example 16 Synthesis of5-chloro-N-(2-methanesulfonylphenyl)-3-methylbenzo[b]thiophene-2-sulfonamide(Compound: 16)

In the same manner as in Example 14, 52 mg of the title compound wasobtained as colorless powder from 100 mg of 2-methanesulfonylaniline.

Melting point: 191-193° C.

¹H-NMR (CDCl₃):δ 2.68 (3H,s), 3.00 (3H,s), 7.24-7.29 (1H,m), 7.35(1H,s), 7.74-7.80 (2H,m), 7.46 (1H,dd,J=1.8,8.6 Hz), 7.74-7.80 (1H,m),7.85 (1H,dd,J=1.5,7.9 Hz).

IR ν_(max)(KBr):3467,3371,3228,3016,2927,2858,1712,1624,1566,1485,1408,1288,1134,1026cm⁻¹.

Example 17 Synthesis of methyl4-(5-fluoro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylbenzoate(Compound 17)

Into 300 mL of THF was dissolved 14.0 g of methyl4-amino-3-methanesulfonylbenzoate, followed by addition of 6.10 g ofsodium hydride (oily, 60%) at 0° C. After 40 minutes of stirring at thesame temperature, 16.0 g of2-chlorosulfonyl-5-fluoro-3-methylbenzo[b]thiophene was added at 0° C.followed by 3 hours of stirring at room temperature. After confirmationof disappearance of the starting material, the reaction was terminatedby adding 2 mol/L hydrochloric acid at 0° C., followed by extractionwith ethyl acetate. The organic layer was washed with saturated aqueoussodium hydrogen carbonate solution and saturated brine and then driedover anhydrous sodium sulfate. The solvent was removed by evaporationand the residue was diluted with ethyl acetate. After the solution wastreated with active carbon, purification by recrystallization (ethylacetate/ether) afforded 24.8 g of the title compound as colorlesspowder.

Melting point: 202-204° C.

¹H-NMR (CDCl₃):δ 2.69 (3H,s), 3.06 (3H,s), 3.90 (3H,s), 7.28(1H,ddd,J=2.6,8.7,8.9 Hz), 7.46 (1H,dd,J=2.6,9.2 Hz), 7.76(1H,dd,J=4.7,8.9 Hz), 7.87 (1H,d,J=8.8 Hz), 8.19 (1H,dd,J=2.0,8.8 Hz),8.50 (1H,d,J=2.0 Hz), 9.83 (1H,s).

IR ν_(max) (KBr):3182,1724,1604,1504,1442,1396,1346,1303,1157 cm⁻¹.

Example 18 Synthesis of methyl4-(5-methyl-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylbenzoate(Compound 18)

Into 8.0 mL of THF was dissolved 183 mg of methyl4-amino-3-methanesulfonylbenzoate, followed by addition of 96 mg ofsodium hydride (oily, 60%) at 0° C. After 20 minutes of stirring at thesame temperature, 250 mg of2-chlorosulfonyl-5-methyl-3-methylbenzo[b]thiophene was added at 0° C.,followed by 6 hours of stirring at room temperature. After confirmationof disappearance of the starting material, the reaction was terminatedby adding 1 mol/L hydrochloric acid at 0° C., followed by extractionwith chloroform. The organic layer was washed with saturated brine andthen dried over anhydrous sodium sulfate. The solvent was removed byevaporation and then the residue was purified by silica gel columnchromatography (ethyl acetate/hexane=3/1 to 1/1) to obtain 181 mg of thetitle compound as colorless powder.

Melting point: 179-181° C.

¹H-NMR (CDCl₃):δ 2.48 (3H,s), 2.70 (3H,s), 3.02 (3H,s), 3.89 (3H,s),7.35 (1H,dd,J=2.2,8.8 Hz), 7.60 (1H,d,J=2.2 Hz), 7.69 (1H,d,J=8.8 Hz),7.88 (1H,d,J=8.8 Hz), 8.18 (1H,dd,J=1.8,8.8 Hz), 8.50 (1H,d,J=1.8 Hz).

IR ν_(max)(KBr):3460,3178,3016,2927,2861,1724,1604,1500,1439,1396,1300,1130,1061cm⁻¹.

Example 19 Synthesis ofN-(4-acetyl-2-methanesulfonylphenyl)-5-fluoro-3-methylbenzo[b]thiophene-2-sulfonamide(Compound 19)

Into a mixed solvent of 168 mL of THF and 42 mL of DMF was dissolved6.30 g of (4-amino-3-methanesulfonyl)acetophenone, followed by additionof 4.70 g of sodium hydride (oily, 60%) at −40° C. After 10 minutes ofstirring at the same temperature, 8.60 g of2-chlorosulfonyl-5-fluoro-3-methylbenzo[b]thiophene was added at thesame temperature, followed by 4 hours of stirring at the sametemperature. After confirmation of disappearance of the startingmaterial, the reaction was terminated by adding 1 mol/L hydrochloricacid at the same temperature and then the mixture was rendered pH 1 withconcentrated hydrochloric acid, followed by extraction with chloroform.The organic layer was washed with saturated brine and then dried overanhydrous sodium sulfate. The solvent was removed by evaporation andthen the residue was diluted with chloroform. After the solution wastreated with active carbon, the solvent was removed by evaporation andthe resulting crystals were washed with methanol to obtain 10.9 g of thetitle compound as colorless powder.

Melting point: 174-175° C.

¹H-NMR (CDCl₃):δ 2.56 (3H,s), 2.69 (3H,s), 3.08 (3H,s), 7.29(1H,ddd,J=2.5,8.8,8.8 Hz), 7.47 (1H,dd,J=2.5,8.8 Hz), 7.77(1H,dd,J=4.6,8.8 Hz), 7.84 (1H,d,J=8.6 Hz), 8.12 (1H,dd,J=2.2,8.6 Hz),8.42 (1H,d,J=2.2 Hz), 9.83 (1H,brs).

IR ν_(max)(KBr):3243,3092,3006,2925,1672,1599,1443,1392,1262,1130,1056,1029 cm⁻¹.

Example 20 Synthesis of methyl4-(3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylbenzoate(Compound 20)

Into a mixed solvent of 30 mL of methanol and 30 mL of dioxane wasdissolved 640 mg of 5% palladium/carbon followed by 10 minutes ofstirring under a hydrogen atmosphere. Under an argon atmosphere, 330 mgof Compound 1 was added, followed by 3 days of stirring under a hydrogenatmosphere at 5 atm. After confirmation of disappearance of the startingmaterial, the reaction mixture was filtered and purified by silica gelcolumn chromatography (ethyl acetate/hexane=2/1) to obtain 70 mg of thetitle compound as colorless powder.

Melting point: 170-172° C.

¹H-NMR (CDCl₃):δ 2.75 (3H,s), 3.04 (3H,s), 3.90 (3H,s), 7.49(1H,dd,J=7.1,7.7 Hz), 7.51 (1H,dd,J=7.1,7.7 Hz), 7.83 (2H,d,J=7.7 Hz),7.89 (1H,d,J=8.8 Hz), 8.20 (1H,dd,J=2.0,8.8 Hz), 8.51 (1H,d,J=2.0 Hz),9.82 (1H,s).

IR ν_(max) (KBr):3209,1720,1604,1500,1442,1392,1350,1308,1165,1122 cm⁻¹.

Example 21 Synthesis of methyl(2S)-2-[4-(5-fluoro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonyl]benzoylamino-3-hydroxy-propionate(Compound 21)

Into 450 mL of chloroform was dissolved 14.3 g of the compound ofReference Example 1. After 7.54 g of L-serine methyl ester hydrochlorideand 9.30 g of EDC hydrochloride were added thereto at room temperature,6.80 mL of triethylamine was added at 0° C. After 2 hours of stirring atthe same temperature, the reaction was terminated by adding 2 mol/Lhydrochloric acid at 0° C. and the mixture was extracted withchloroform. The organic layer was washed with saturated brine and thendried over anhydrous sodium sulfate. The solvent was removed byevaporation and the residue was purified by silica gel columnchromatography (ethyl acetate) to obtain 12.9 g of the title compound ascolorless amorphous.

¹H-NMR (CDCl₃):δ 2.71 (3H,s), 3.07 (3H,s), 3.81 (3H,s), 4.00(1H,dd,J=4.2,11.4 Hz), 4.15 (1H,dd,J=5.4,11.4 Hz), 4.85 (1H,dd,J=4.2,5.4Hz), 7.33 (1H,dd,J=2.1,8.6 Hz), 7.48 (1H,dd,J=2.1,8.6 Hz), 7.79(1H,dd,J=4.6,8.6 Hz), 7.87 (1H,d,J=8.8 Hz), 8.00 (1H,dd,J=2.1,8.8 Hz),8.32 (1H,d,J=2.1 Hz), 9.76 (1H,s).

IR ν_(max) (KBr):3401,1735,1655,1606,1510,1491,1440,1353,1308,1164,1136cm⁻¹.

Example 22 Synthesis of methyl2-[4-(5-fluoro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylphenyl]-4,5-dihydro-oxazole-4-carboxylate(Compound 22)

Into 180 mL of THF was dissolved 12.9 g of Compound 21, and 6.80 g ofBurgess reagent (J. Org. Chem., 38, 26, (1973); J. Org. Chem., 58, 4494(1993)) was added, followed by 2 hours of stirring at 60° C. Afterconfirmation of disappearance of the starting material, the solvent wasremoved by evaporation and water was added, followed by extraction withethyl acetate. The organic layer was washed with saturated brine andthen dried over anhydrous sodium sulfate. The solvent was removed byevaporation and the residue was purified by silica gel columnchromatography (ethyl acetate/hexane=9/1) to obtain 9.92 g of the titlecompound as colorless amorphous.

¹H-NMR (CDCl₃):δ 2.68 (3H,s), 3.02 (3H,s), 3.81 (3H,s), 4.60(1H,dd,J=9.0,10.6 Hz), 4.69 (1H,dd,J=7.9,9.0 Hz), 4.93 (1H,dd,J=7.9,10.6Hz), 7.29 (1H,ddd,J=2.1,8.8,8.8 Hz), 7.46 (1H,dd,J=2.1,8.8 Hz), 7.76(1H,dd,J=4.6,8.8 Hz), 7.87 (1H,d,J=8.8 Hz), 8.15 (1H,dd,J=2.1,8.8 Hz),8.43 (1H,d,J=2.1 Hz), 9.81 (1H,s).

IR ν_(max)(KBr):3226,1737,1647,1608,1498,1441,1395,1355,1308,1248,1211,1164 cm⁻¹.

Example 23 Synthesis of methyl2-[4-(5-fluoro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylphenyl]oxazole-4-carboxylate(Compound 23)

Into 40 mL of dichloromethane was dissolved 1.10 g of Compound 22,followed by addition of 498 mg of bromotrichloromethane at −20° C.Further, 700 mg of DBU was added dropwise at the same temperature andthe whole was stirred at the same temperature for 5 minutes and thenwarmed to 0° C., followed by 3.5 hours of stirring. After confirmationof disappearance of the starting material, the reaction was terminatedby adding saturated aqueous sodium hydrogen carbonate solution at 0° C.,followed by extraction with ethyl acetate. The organic layer was washedwith saturated brine and then dried over anhydrous magnesium sulfate.The solvent was removed by evaporation and the residue was purified bysilica gel column chromatography (ethyl acetate/methanol=20/1) to obtain597 mg of the title compound as colorless powder.

Melting point: 290-292° C.

¹H-NMR (CDCl₃):δ 2.70 (3H,s), 3.06 (3H,s), 3.95 (3H,s) (7.30(1H,ddd,J=2.4,8.7,8.7 Hz), 7.47 (1H,dd,J=2.4,9.0 Hz), 7.77(1H,dd,J=4.8,9.0 Hz), 7.94 (1H,d,J=9.0 Hz), 8.27 (1H,s), 8.28(1H,dd,J=2.1,9.0 Hz), 8.57 (1H,d,J=2.1 Hz), 9.78 (1H,s).

IR ν_(max)(KBr):3243,1720,1618,1590,1518,1485,1440,1355,1320,1303,1259,1162,1136cm⁻¹.

Example 24 Synthesis of2-[4-(5-fluoro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylphenyl]oxazole-4-carboxylicAcid (Compound 24)

Into 150 mL of methanol was dissolved 7.85 g of Compound 23, and 15 mLof 10% aqueous sodium hydroxide solution and 15 mL of water were addedthereto at room temperature, followed by 15 minutes of stirring. Theprecipitated crystals were dissolved by adding 90 mL of water, and thesolution was stirred at the same temperature for 17 hours. After thesolvent was removed by evaporation, 45 mL of 1 mol/L hydrochloric acidwas added to the residue, the precipitated crystals were collected byfiltration and washed with water, and 100 mL of DMF was added to theresulting crude crystals, followed by heating under refluxing. Afterfiltration at a hot state, 70 mL of ethanol was added andrecrystallization was carried out. The resulting crystals were collectedby filtration, washed several times with ethanol and wateralternatively, and dried over diphosphorus pentoxide under reducedpressure to obtain 5.78 g of the title compound as colorless powder.

Melting point: 289-291° C.

¹H-NMR (DMSO-d₆):δ 2.55 (3H,s), 3.41 (3H,s), 7.44 (1H,ddd,J=1.8,8.7,9.0Hz), 7.64 (1H,d,J=8.4 Hz), 7.79 (1H,dd,J=1.8,9.9 Hz), 8.08(1H,dd,J=4.8,8.7 Hz), 8.19 (1H,dd,J=1.8,8.4 Hz), 8.41 (1H,d,J=1.8 Hz),8.84 (1H,s).

IR ν_(max) (KBr):3232,1717,1690,1616,1487,1440,1355,1313,1161,1140 cm⁻¹.

Example 25 Synthesis of methyl2-[4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylphenyl]oxazole-4-carboxylate(Compound 25)

Into 10 mL of dichloromethane was dissolved 495 mg of copper dibromide,followed by addition of 310 mg of hexamethyltetramine at roomtemperature. Further, 337 mg of DBU was added dropwise at 0° C., thewhole was stirred at the same temperature for 5 minutes and then 300 mgof Compound 47 was added at 0° C., followed by 3 hours of stirring atroom temperature. After confirmation of disappearance of the startingmaterial, ethyl acetate was added to the reaction mixture. The organiclayer was washed with a 1:1 mixed solution of saturated aqueous ammoniumchloride solution and 25% aqueous ammonia solution, saturated aqueoussodium hydrogen carbonate and saturated brine and then dried overanhydrous magnesium sulfate. The solvent was removed by evaporation andthe residue was purified by silica gel column chromatography(chloroform/methanol=10/1) to obtain 110 mg of the title compound ascolorless powder.

Melting point: 237-239° C.

¹H-NMR (CDCl₃):δ 2.70 (3H,s), 3.05 (3H,s), 3.95 (3H,s), 7.47(1H,dd,J=2.1,8.7 Hz), 7.74 (1H,d,J=8.7 Hz), 7.79 (1H,d,J=2.1 Hz), 7.93(1H,d,J=9.0 Hz), 8.27 (1H,s), 8.28 (1H,dd,J=2.1,9.0 Hz), 8.56(1H,d,J=2.1 Hz), 9.72 (1H,brs).

IR ν_(max) (KBr):3231,1744,1486,1317,1136 cm¹.

Example 26 Synthesis of2-[4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylphenyl]oxazole-4-carboxylicAcid (Compound 26)

In the same manner as in Example 24, 68 mg of the title compound wasobtained as colorless powder from 70 mg of Compound 25.

Melting point: 296-298° C.

¹H-NMR (DMSO-d₆):δ 2.58 (3H,s), 3.37 (3H,s), 7.55 (1H,dd,J=2.1,8.7 Hz),7.62 (1H,d,J=8.7 Hz), 8.01 (1H,d,J=2.1 Hz), 8.09 (1H,d,J=8.4 Hz), 8.12(1H,dd,J=2.1,8.4 Hz), 8.40 (1H,d,J=2.1 Hz), 8.83 (1H,s).

IR ν_(max) (KBr):3221,2924,1701,1485,1311,1153 cm⁻¹.

Example 27 Synthesis of disodium2-[4-(5-fluoro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylphenyl]oxazole-4-carboxylate(Compound 27)

Into 30 mL of methanol was dissolved 290 mg of Compound 23, followed byaddition of 77 mg of sodium methoxide. After 8 hours of stirring at roomtemperature, ether was added and the precipitated crystals werecollected by filtration and washed with ether to obtain 300 mg of thetitle compound as colorless powder.

Melting point: 341-343° C.

¹H-NMR (DMSO-d₆):δ 2.49 (3H,s), 3.42 (3H,s), 7.26 (1H,ddd,J=2.4,8.8,9.0Hz), 7.40 (1H,dd,J=9.0,9.0 Hz), 7.56 (1H,dd,J=2.4,8.9 Hz), 7.89(1H,dd,J=2.2,9.0 Hz), 7.95 (1H,d,J=9.0 Hz), 8.19 (1H,d,J=2.2 Hz).

IR ν_(max) (KBr):3490,1609,1570,1523,1470,1441,1400,1302,1280,1119 cm⁻¹.

In the following, Compounds 28 to 49 of Examples 28 to were synthesizedin the same manner as in Example 1.

TABLE 1 (I)

Example R¹ R² R³ R⁴ R⁵ 28 Cl Me H NO₂ H 29 Cl Me H CN H 30 Cl Me H COMeH 31 Cl Me H CONH₂ H 32 Cl Me H COCH₂SCH₂CO₂Me H 33 Cl Me OMe NO₂ H 34Cl Me NO₂ CN H 35 Cl Me NO₂ NO₂ H 36 Cl Me NO₂ OMe H 37 Cl Me OMeCONHCH₂CO₂Et H 38 Cl Me CO₂Me OMe OMe 39 Cl Me H SO₂(CH₂)₂CH₃ H 40 H MeH SO₂(CH₂)₂CH₃ H 41 Me Me H SO₂(CH₂)₂CH₃ H 42 Cl Me SO₂Me CO₂CH(CH₃)₂ H43 Cl Me SO₂Me CONHCH₂CO₂Et H 44 Cl Me SO₂Me

H

TABLE 2 (I)

Example R¹ R² R³ R⁴ R⁵ 45 Cl Me SO₂Me

H 46 Cl Me SO₂Me

H 47 Cl Me SO₂Me

H 48 F Me SO₂Me

H 49 F Me SO₂NEt₂ CO₂Me H

Example 50 Synthesis of2-[4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methoxybenzoylamino]aceticAcid (Compound 50)

Into 25 mL of ethanol was dissolved 104 mg of Compound 37, and 1 mL of 1mol/L aqueous sodium hydroxide solution was added at room temperature,followed by 15 hours of stirring at the same temperature. Afterconfirmation of disappearance of the starting material, the solvent wasremoved by evaporation, followed by extraction with ether. After 2 mol/Lhydrochloric acid was added to the aqueous layer, the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and then dried over anhydrous sodium sulfate. Thesolvent was removed by evaporation and the resulting powder was washedwith ether to obtain 97 mg of the title compound as light yellow powder.Melting point: 282-285° C.

¹H-NMR (CDCl₃/CD₃OD):δ 2.50 (3H,s), 3.82 (2H,s), 3.84 (3H,s), 7.10-7.15(2H,m), 7.20-7.35 (2H,m), 7.60-7.70 (2H,m).

IR ν_(max) (KBr):3394,2974,1604,1554,1493,1412,1284,1230,1130 cm⁻¹.

Example 51 Synthesis of sodium methyl4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylbenzoate(Compound 51)

Into 8 mL of THF was dissolved 115 mg of Compound 1, followed byaddition of 15 mg of sodium hydride (oily, 60%) at room temperature.After 1.5 hours of stirring at the same temperature, the solvent wasremoved by evaporation and the resulting powder was washed with ether toobtain 61 mg of the title compound as colorless powder.

Melting point: >300° C.

¹H-NMR (DMSO-d₆):δ 2.51 (3H,s), 3.37 (3H,s), 3.72 (3H,s), 7.39(1H,d,J=2.1,8.8 Hz), 7.40 (1H,dd,J=1.8,8.5 Hz), 7.68 (1H,dd,J=1.8,8.8Hz), 7.80 (1H,d,J=1.8 Hz), 7.93 (1H,d,J=8.5 Hz), 8.23 (1H,d,J=1.8Hz).

IR ν_(max) (KBr):3448,1705,1597,1481,1442,1292,1134,1103 cm⁻¹.

After Compound 43, 44 and 46 were subjected to ester hydrolysis, theproducts were converted into sodium salts in the same conditions as inExample 51 to synthesize Compounds 52, 53 and 54 of Examples 52, 53 and54.

TABLE 3 (I)

Example R¹ R² R³ R⁴ R⁵ 52 Cl Me SO₂Me CONHCH₂CO₂Na H 53 Cl Me SO₂Me

H 54 Cl Me SO₂Me

H

The following show instrumental data in each Examples.

TABLE 4 Ex- Melting am- point IR ple (° C.) H¹-NMR (δ) (ν cm⁻¹, KBr) 28Amorph- CDCl₃ 2.62 (3H, s), 7.29 (2H, d, 3248, 3084, ous J = 9.1 Hz),7.46 (1H, dd, 2925, 2856, J = 2.0, 8.7 Hz), 7.47 1596, 1521, (1H, brs),7.73 (1H, d, 1342, 1160, J = 8.7 Hz), 7.76(1H, d, J = 1113 2.0 Hz), 8.15(2H, d, J = 9.1 Hz) 29 226-227 CDCl₃/ 2.60 (3H,s), 7.29 (2H, d, 3236,2222, CD₃OD J = 9.0 Hz), 7.45(1H, dd, 1606, 1508, J = 2.1, 8.7 Hz),7.53(2H, 1469, 1356, d, J = 9.0 Hz), 7.75(1H, d, 1160 J = 2.1 Hz),7.76-7.77(1H, m) 30 223-225 CDCl₃ 2.53 (3H, s), 2.54 (3H, s), 3178,2927, 7.20-7.23 (2H, m), 7.45 2233, 1666, (1H, dd, J = 2.1, 8.6 Hz),1593, 1508, 7.72 (2H, d, J = 8.6 Hz), 1404, 1338, 7.88 (2H, d, 8.6 Hz)1273, 1153 31 254-258 CDCl₃ 2.55 (3H, s), 7.24 (2H, d, 3379, 3255, J =7.4 Hz),7.36-7.45 3174, 2911, (3H, m), 7.72 (2H, d, 2846, 2765, J = 8.6Hz) 1651, 1512, 1404, 1335, 1223, 1157 32 151-153 CDCl₃ 2.57 (3H, s),3.30 (2H, s), 3221, 3059, 3.71 (3H, s), 3.93 (2H, s), 2935, 1736,7.20-7.25 (2H, m), 7.44- 1662, 1593, 7.47 (1H, m), 7.71-7.75 1512, 1466,(2H, m), 7.86-7.90 (2H, 1404, 1338, m) 1296, 1153 33 188-190 CDCl₃ 2.63(3H, s), 3.92 (3H, s), 3293, 3088, 7.45 (1H, dd, J = 2.0, 2930, 2846,8.8 Hz), 7.63 (1H, brs), 1735, 1596, 7.67 (1H, d, J = 2.4 Hz), 1525,1500, 7.71 (1H, d, J = 8.8 Hz), 1442, 1402, 7.76 (1H, d, J = 2.0 Hz),1342, 1281, 7.84 (1H, dd, J = 2.4, 1254, 1163, 8.8 Hz) 1130

TABLE 5 Ex- Melting am- point IR ple (° C.) H¹-NMR (δ) (ν cm⁻¹, KBr) 34204-206 CDCl₃ 2.71 (3H,s), 7.51 (1H, dd, 3234, 3081, J = 2.0, 8.6 Hz),7.76 (1H, 2923, 2235, d, J = 8.6 Hz), 7.83 (1H, 1620, 1561, dd, J = 2.0,8.8 Hz), 7.85 1538, 1499, (1H, d, J = 2.0 Hz), 8.12 1415, 1360, (1H, d,J = 8.8 Hz) 8.51 1324, 1278, (1H, d, J = 2.0 Hz) 1164, 1145, 1113 35162-164 CDCl₃ 2.71 (3H, s), 7.50 (1H,dd, 3398, 3232, J = 2.0, 8.6 Hz),7.74(1H, 1604, 1493, d, J = 8.6 Hz), 7.80 (1H, 1423, 1346, d, J = 2.0Hz), 8.15 (1H, 1165 d, J = 9.4 Hz), 8.43 (1H, dd, J = 2.5, 9.4 Hz), 9.08(1H, d, J = 2.5 Hz) 36 120-122 CDCl₃ 2.52 (3H, s), 3.82 (3H,s), 3325,3078, 7.18-7.22 (1H, m), 7.42- 2931, 2838, 7.50 (2H, m), 7.67-7.73 1905,1619, (2H, m), 7.88 (1H, d, 15.23,1439, J = 9.2 Hz) 1346, 1265, 1153 37196-198 CDCl₃ 1.30 (3H, t, J = 7.2 Hz), 3278, 1743, 2.55 (3H, s), 3.77(3H, s), 1639, 1550, 4.18 (2H, d, J = 4.9 Hz), 1508, 1408, 4.25 (2H, q,J = 7.2 Hz), 1350, 1215, 7.33 (1H, d, J = 1.8 Hz), 1165 7.40-7.45 (2H,m), 7.60- 7.75 (3H, m) 38 203-205 CDCl₃ 2.56 (3H, s), 3.82 (6H, s),3444, 3170, 3.96 (3H, s), 7.30 (1H, s), 2947, 1678, 7.41 (1H, s),7.39-7.44 1612, 1520, (1H, m), 7.67 (1H, s), 1442, 1362, 7.68-7.75 (1H,m) 1257, 1207, 1161 39 181-183 CDCl₃ 0.96 (3H, t, J = 7.6 Hz), 3217,2966, 1.69 (2H, sext, J = 7.6 Hz), 1593, 1493, 2.58 (3H, s), 3.00 (2H,t, 1404, 1350, J = 7.6 Hz), 7.31 (2H, d, 1288, 1238, J = 8.8 Hz), 7.47(1H, dd, 1142, 1088 J = 2.1, 8.7 Hz), 7.72 (1H, d, J = 8.7 Hz), 7.74(1H, d, J = 2.1 Hz), 7.79 (2H, d, J = 8.8 Hz)

TABLE 6 Ex- Melting am- point IR ple (° C.) H¹-NMR (δ) (ν cm⁻¹, KBr) 40201-203 CDCl₃ 0.95 (3H, t, J = 7.9 Hz), 3195, 3058, 1.66 (2H, sext, J =7.9 Hz), 2930, 2878, 2.67 (3H, s), 3.05 (2H, t, 1594, 1497, J = 7.9 Hz),7.40 (2H, d, 1489, 1346, J = 9.0 Hz), 7.47 (1H, td, 1281, 1160, J = 1.5,7.9 Hz), 7.51 (1H, 1132 td, J = 1.5, 7.9 Hz), 7.74 (2H, d, J = 9.0 Hz),7.84 (2H, dt, J = 1.5, 7.9 Hz) 41 201-203 CDCl₃ 0.96 (3H, t, J = 7.7Hz), 3194, 3059, 1.69 (2H, sext, J = 7.7 Hz), 2962, 2877, 2.49 (3H, s),2.59 (3H, s), 1593, 1493, 3.00 (2H, t, J = 7.7 Hz), 1400, 1342, 7.11(1H, s), 7.30 (2H, d, 1292, 1138 J = 8.6 Hz), 7.34 (1H, d, J = 8.4 Hz),7.56 (1H, s), 7.68 (1H, d, J = 8.4 Hz), 7.78 (2H, d, J = 8.6 Hz) 42164-166 CDCl₃ 1.33 (6H, d, J = 6.2 Hz), 3410, 3244, 2.70 (3H, s), 3.06(3H, s), 2924, 1709, 5.22 (1H, q, 6.2 Hz), 7.47 1604, 1500, (1H, dd, J=2.1, 8.8 Hz), 1350, 1304, 7.74 (1H, d, J = 8.8 Hz), 1153 7.79 (1H, d, J= 1.5 Hz), 7.85 (1H, d, J = 8.6 Hz), 8.18 (1H, d, J = 8.6 Hz), 8.48 (1H,d, J = 1.5 Hz), 9.82 (1H, s) 43 88-90 CD₃OD 1.25 (3H, t, J = 7.2 Hz),3359, 3232, 2.64 (3H, s), 3.19 (3H, 3078, 2989, brs), 4.05 (2H, s), 4.172927, 1739, (2H, q, J = 7.2 Hz) 7.45 1655, 1604, (1H, d, J = 8.7 Hz),7.75 1485, 1304, (1H, brd, J = 6.9 Hz), 7.85 1211, 1161, (1H, d, J = 8.7Hz), 7.87 1134 (1H, s), 7.96 (1H, brd, J = 6.9 Hz), 8.34 (1H, d, J = 1.8Hz)

TABLE 7 Ex- Melting am- point IR ple (° C.) H¹-NMR (δ) (ν cm⁻¹, KBr) 44154-156 CD₃OD 2.65 (3H, s), 3.07 (3H, s), 3220, 2924, 3.73 (3H, s), 3.89(1H, dd, 1736, 1643, J = 4.2 Hz, 11.4 Hz), 3.95 1608, 1496, (1H, dd, J =5.4, 11.4 Hz), 1303, 1161, 4.68 (1H, dd, J = 4.2, 1130 5.4 Hz), 7.47(1H, dd, J = 2.1, 8.4 Hz), 7.85 (2H, dd, J = 2.1, 8.7 Hz), 7.91 (H, d, J= 2.1 Hz), 8.09 (1H, dd, J = 2.1, 8.7 Hz), 8.36 (1H, d, J = 2.1 Hz) 45Amorph- CDCl₃ 2.10 (3H, s), 2.20 (2H, 3230, 2921, ous m), 2.56 (2H, m),2.70 2853, 1739, (3H, S), 3.05 (3H, s), 1653, 1604, 3.78 (3H, s), 4.89(1H, 1541, 1492, m), 7.09 (1H, brs), 1440, 1393, 7.48 (1H, brm), 7.871353, 1307, (2H, m), 7.96 (1H, m) , 1226, 1166, 8.29 (1H, brs), 9.731131, 1105 (1H, brs) 46 Amorph- CDCl₃ 2.00-2.30 (4H, m), 2.70 3228,2952, ous (3H, s), 2.98 (3H, s), 2925, 1741, 3.50-3.65 (2H, m), 3.761631, 1496, (3H, s), 4.61 (1H, m), 1423, 1390, 7.48(1H, d, J = 8.4 Hz),1353, 1308, 7.75(1H, d, J = 8.4 Hz), 1281, 1203, 7.70-7.80 (3H, m),1167, 1133, 8.10 (1H, s), 9.69 1107, 1080 (1H, brs) 47 Amorph- CDCl₃2.69 (3H, s), 3.01 (3H, 3224, 2958, ous s), 3.80 (3H, s), 4.58 1739,(1H, dd, J = 9.0, 10.5 1500, 1308, Hz), 4.68 (1H, dd, 1161 J = 8.1, 9.0Hz), 4.93 (1H, dd, J = 8.1, 10.5 Hz), 7.47 (1H, dd, J = 2.1, 8.4 Hz),7.73 (1H, d, J = 8.4 Hz), 7.78 (1H, d, J = 2.1 Hz), 7.86 (1H, d, J = 8.7Hz), 8.14 (1H, dd, J = 2.1, 8.7 Hz), 8.43 (1H, d, J = 2.1 Hz)

TABLE 8 Ex- Melting am- point IR ple (° C.) H¹-NMR (δ) (ν cm⁻¹, KBr) 48199-201 DMSO- 2.51 (3H, s), 3.17 (3H, 3243, 3119, d₆ s), 7.46 (1H, ddd,1606, 1501, J = 1.8, 9.0, 9.0 Hz), 1303, 1151 7.52 (1H, d, J = 8.4 Hz),7.75 (1H, d, J = 1.8 Hz), 7.81 (1H, dd, J = 1.8, 8.7 Hz), 7.98 (1H, dd,J = 1.8, 8.4 Hz), 8.10 (1H, dd, J = 4.8, 9.0 Hz), 8.15 (1H, s) , 8.48(1H, s) 49 137-140 CDCl₃ 1.14 (6H, t, J = 7.1 Hz), 3157, 3076, 2.68 (3H,s), 3.31 (4H, 2979, 2949, q, J = 7.1 Hz), 3.88 (3H, 1727, 1604, s), 7.29(1H, ddd, 1577, 1560, J = 2.1, 8.8, 8.8 Hz), 1521, 1498, 7.45 (1H, dd, J= 2.1, 1473, 1458, 8.8 Hz), 7.75 (1H, dd, 1438, 1389, J = 4.8, 8.8 Hz),7.84 1344, 1325, (1H, d, J = 8.6 Hz), 8.07 1307, 1280, (1H, dd, J = 2.0,8.6 1200, 1159, Hz), 8.35 (1H, d, J = 2.0 1134, 1100 Hz), 9.88 (1H, s)52 290-292 D₂O 2.50 (3H, s), 3.47 (3H, s), 3410, 1600, 3.82 (2H,s), 7.22(1H, d, 1473, 1400, J = 8.7 Hz), 7.42 (1H, dd, 1296, 1134, J = 1.8, 8.7Hz), 7.69 (1H, 1107 dd, J= 2.1, 8.7 Hz), 7.80 (1H, d, J = 8.7 Hz), 7.83(1H, d, J = 2.1 Hz), 8.21 (1H, d, J = 1.8 Hz) 53 260 D₂O 2.47 (3H, s),3.48 (3H, s), 3464, 1597, 3.81 (1H, dd, J = 5.7 Hz, 1473, 1408, 11.4Hz), 3.87 (1H, dd, J = 1292, 1134, 3.6, 11.4 Hz), 4.38 (1H, dd, 1107 J =3.6, 5.7 Hz), 7.24 (1H, d, 8.7 Hz), 7.33 (1H, d, J = 8.7 Hz), 7.68-7.73(3H, m), 8.24 (1H, d, J = 2.1 Hz)

TABLE 9 Ex- Melting am- point IR ple (° C.) H¹-NMR (δ) (ν cm⁻¹, KBr) 54298 D₂O 1.66-1.78 (2H, m), 2.06- 3419, 1599, 2.12 (2H, m), 2.32 (3H,1436, 1308, s), 3.43 (3H, s), 3.37-3.48 1105 (2H, m), 4.14 (1H, m), 6.99(1H, d, J = 8.7 Hz), 7.10-7.25 (2H, m), 7.34- 7.40 (2H, m), 7.51 (1H, d,J = 8.7 Hz), 7.95 (1H, d, J = 1.8 Hz)

Example 55 Synthesis of5-fluoro-N-[2-methanesulfonyl-4-(5-methoxy-4-methylthiazol-2-yl)phenyl]-3-methylbenzo[b]thiophene-2-sulfonamide(Compound 55)

Under an argon atmosphere, 41 mg of2-methanesulfonyl-4-(5-methoxy-4-methylthiazol-2-yl)aniline wasdissolved into a mixed solution of 3 mL of THF and 3 mL ofdimethylacetamide. The solution was cooled to −25° C. and 15 mg ofsodium hydride (oily, 60%) was added thereto, followed by 10 minutes ofstirring at the same temperature. Further, 44 mg of2-chlorosulfonyl-5-fluoro-3-methylbenzo[b]thiophene was added and thewhole was stirred for 2 hours at the same temperature, followed bytermination of the reaction with 1 mol/L hydrochloric acid. After thereaction mixture was warmed to room temperature, the mixture wasextracted with ethyl acetate-toluene (2/1) and the organic layer waswashed with water and saturated brine, successively. After the organiclayer was dried over anhydrous sodium sulfate, the solvent was removedby evaporation under reduced pressure and the resulting residue waspurified by silica gel column chromatography (ethyl acetate/hexane=1/1)to obtain 51 mg of the title compound as light yellow powder.

Melting point: 216-217° C.

¹H-NMR (CDCl₃):δ 2.29 (3H,s), 2.68 (3H,s), 2.99 (3H,s), 3.93 (3H,s),7.27 (1H,ddd,J=2.6,8.6,8.8 Hz), 7.46 (1H,dd,J=2.6,9.2 Hz), 7.75(1H,dd,J=4.7,8.8 Hz), 7.82 (1H,d,J=8.7 Hz), 7.96 (1H,dd,J=2.1,8.7 Hz),8.25 (1H,d,J=2.1 Hz), 9.57 (1H,s).

IR ν_(max)(KBr):3202,2989,2910,1604,1558,1501,1441,1349,1298,1253,1156,1133,926cm⁻¹.

Example 56 Synthesis of5-fluoro-N-[2-methanesulfonyl-4-(5-methoxy-4-methyloxazol-2-yl)phenyl]-3-methylbenzo[b]thiophene-2-sulfonamide(Compound 56)

Into 26 mL of phosphorus oxychloride was added 5.28 g of the compound ofReference Example 2, followed by 3 hours of heating under refluxing.After the reaction mixture was cooled to room temperature, the mixturewas poured into ice and extracted with chloroform. The organic layer waswashed with water and saturated brine, successively and dried overanhydrous sodium sulfate. The solvent was removed by evaporation underreduced pressure and the resulting residue was purified by silica gelcolumn chromatography (chloroform) to obtain 2.02 g of the titlecompound as colorless powder.

Melting point: 232-233° C.

¹H-NMR (DMSO-d₆):δ 82.02 (3H,s), 2.57 (3H,s), 3.32 (3H,s), 3.96 (3H,s),7.46 (1H,ddd,J=2.5,9.0,9.0 Hz), 7.54 (1H,d,J=8.4 Hz), 7.81(1H,dd,J=2.5,9.9 Hz), 8.06 (1H,dd,J=1.9,8.4 Hz) j, 8.10 (1H,dd,J=4.9,9.0Hz), 8.26 (1H,d,J=1.9 Hz).

IR ν_(max)(KBr):3253,3083,3000,2922,1665,1491,1442,1393,1354,1308,1169,1131 cm⁻¹.

Example 57 Synthesis of5-fluoro-N-[2-methanesulfonyl-4-(5-methylthiazol-2-yl)phenyl]-3-methylbenzo[b]thiophene-2-sulfonamide(Compound 57)

Into 5 mL of 1,4-dioxane solution of 150 mg of4-(5-fluoro-3-methylbenzo[b]thiophene-2-yl)sulfonamido-3-methanesulfonyl-N-(2-oxopropyl)benzamidewas added 135 mg of diphosphorus pentasulfide, followed by 4.5 hours ofheating under refluxing. The reaction was terminated by adding water tothe reaction mixture and the mixture was extracted with ethyl acetate.The organic layer was washed with water and saturated brine,successively and then dried over anhydrous sodium sulfate. The solventwas removed by evaporation under reduced pressure and the resultingresidue was purified by silica gel column chromatography (hexane/ethylacetate=2/1 to 1/1) to obtain 115 mg of the title compound as amorphous.

¹H-NMR (CDCl₃):δ2.51 (3H,s), 2.69 (3H,s), 3.02 (3H,s), 7.27(1H,ddd,J=2.4,8.6,8.9 Hz), 7.47 (1H,dd,J=2.4,9.2 Hz), 7.50 (1H,s), 7.76(1H,dd,J=4.8,8.9 Hz), 7.86 (1H,d,J=8.8 Hz), 8.05 (1H,dd,J=2.1,8.8 Hz),8.35 (1H,d,J=2.1 Hz), 9.64 (1H,s).

IR ν_(max) (KBr):3240,3010,2926,1607,1499,1353,1302,1160,994 cm⁻¹.

In the following, the compounds 58 to 62 of Examples 58 to 62 weresynthesized in the same manner as in Examples 56 and 57.

TABLE 10 (I)

Example R¹ R² R³ R⁴ R⁵ 58 Cl Me SO₂Me

H 59 F Me SO₂Me

H 60 F Me SO₂Me

H 61 F Me SO₂Me

H 62 F Me SO₂Me

H

Example 63 Synthesis of5-fluoro-N-[4-(4-hydroxymethylthiazol-2-yl)-2-methanesulfonylphenyl]-3-methylbenzo[b]thiophene-2-sulfonamide(Compound 63)

Into 226 mL of THF suspension of 298 mg of lithium aluminum hydride wasadded dropwise 452 mL of THF solution of 4.52 g of Compound 69, followedby 6 hours of stirring at room temperature. Further, 298 mg of lithiumaluminum hydride was added thereto, followed by 14 hours of stirring atroom temperature. After confirmation of disappearance of the startingmaterial, the reaction was terminated by adding 10 mL of water at 10° C.and the mixture was stirred for 30 minutes. The solvent was removed byevaporation under reduced pressure and chloroform was added to theresulting residue. The organic layer was washed with 1 mol/L sulfuricacid, water and saturated brine, successively and then dried overanhydrous sodium sulfate. The solvent was removed by evaporation underreduced pressure and the resulting residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane=1/1). To the resultingcrystals were added 140 mL of chloroform and 28 mL of hexane, followedby heating under refluxing. After filtration at a hot state, thecrystals obtained by recrystallization were collected by filtration anddried under reduced pressure to obtain 2.58 g of the title compound aslight yellow powder.

Melting point: 209-210° C.

¹H-NMR (CDCl₃):δ 2.69 (3H,s), 3.04 (3H,s), 4.80 (2H,s), 7.22 (1H,s),7.27 (1H,ddd,J=2.4,8.6,8.8 Hz), 7.47 (1H,dd,J=2.4,9.2 Hz), 7.76(1H,dd,J=4.7,8.8 Hz), 7.88 (1H,d,J=8.8 Hz), 8.09 (1H,dd,J=2.2,8.8 Hz),8.42 (1H,d,J=2.2 Hz), 9.65 (1H,s).

IR ν_(max)(KBr):3423,3237,3114,3026,2930,1605,1509,1445,1354,1294,1152,1135 cm⁻¹.

Example 64 Synthesis ofN-[4-(4-chloromethylthiazol-2-yl)-2-methanesulfonylphenyl]-5-fluoro-3-methylbenzo[b]thiophene-2-sulfonamide(Compound 64)

Into 20 mL of chloroform was suspended 159 mg of Compound 63, and 47 μLof thionyl chloride was added at 0° C., followed by 21 hours of stirringat room temperature. Further, 1 mL of thionyl chloride was added,followed by 1 hour of heating under refluxing. After 2 mL oftriethylamine was added at 0° C. and the mixture was stirred for 3hours, the reaction was terminated with 1 mol/L hydrochloric acid,followed by extraction with ethyl acetate. The organic layer was washedwith water and saturated brine, successively and then dried overanhydrous sodium sulfate. The solvent was removed by evaporation underreduced pressure and the resulting residue was purified by silica gelcolumn chromatography (chloroform) to obtain 104 mg of the titlecompound as light brown powder.

Melting point: 190-191° C.

¹H-NMR (CDCl₃):δ 2.69 (3H,s), 3.04 (3H,s), 4.70 (2H,s), 7.28(1H,ddd,J=2.5,8.6,8.8 Hz), 7.34 (1H,s), 7.47 (1H,dd,J=2.5,9.2 Hz), 7.76(1H,dd,J=4.7,8.8 Hz), 7.89 (1H,d,J=8.8 Hz), 8.11 (1H,dd,J=2.2,8.8 Hz),8.41 (1H,d,J=2.2 Hz), 9.66 (1H,s).

IR ν_(max)(KBr):3236,3098,3027,2927,1607,1507,1457,1354,1306,1156,1137,912 cm⁻¹.

Example 65 Synthesis of5-fluoro-N-[2-methanesulfonylbenzoate-4-(4-methylthiazol-2-yl)phenyl]-3-methylbenzo[b]thiophene-2-sulfonamide(Compound 65)

Into 10 mL of acetone was dissolved 64 mg of Compound 64, and 180 mg ofsodium iodide was added, followed by 24 hours of heating underrefluxing. Further, 180 mg of sodium iodide was added and the mixturewas heated under refluxing for 19 hours. The solvent was removed byevaporation under reduced pressure and the residue was dissolved intoethyl acetate. The solution was washed with water, 5% aqueous sodiumthiosulfate solution, water and saturated brine, successively, and thendried over anhydrous sodium sulfate. After the solvent was removed byevaporation under reduced pressure, the resulting5-fluoro-N-[4-(4-iodomethylthiazol-2-yl)-2-methanesulfonylphenyl]-3-methylbenzo[b]thiophene-2-sulfonamidewas dissolved into a mixed solution of 5 mL of toluene and 0.5 mL ofDMSO, and 45 μL of tributyltin hydride and 13 μL of 1.06 mol/L hexanesolution of triethylboron were added, followed by 6 hours of stirring atroom temperature. Further, 24 μl of tributyltin hydride was added andthe mixture was stirred at room temperature for 3 hours. Then, thereaction was terminated by adding saturated aqueous ammonium chloridesolution, followed by extraction with ethyl acetate. The organic layerwas washed with water and saturated brine, successively, and then driedover anhydrous sodium sulfate. The solvent was removed by evaporationunder reduced pressure and the resulting residue was purified by silicagel column chromatography (hexane to hexane/ethyl acetate=3/1) to obtain29 mg of the title compound as colorless powder.

Melting point: 199-200° C.

¹H-NMR (CDCl₃):δ 2.48 (3H,s), 2.69 (3H,s), 3.03 (3H,s), 6.91 (1H,s),7.27 (1H,ddd,J=2.4,8.6,8.8 Hz), 7.46 (1H,dd,J=2.4,9.2 Hz), 7.75(1H,dd,J=4.7,8.8 Hz), 7.87 (1H,d,J=8.7 Hz), 8.09 (1H,dd,J=2.1,8.7 Hz),8.40 (1H,d,J=2.1Hz), 9.65 (1H,s).

IR ν_(max)(KBr):3243,3105,3028,2925,1607,1508,1442,1355,1308,1162,1135,913 cm⁻¹.

In the following, Compounds 66 to 68 of Examples 66 to 68 weresynthesized in the same manner in Examples 63 to 65.

TABLE 11 (I)

Example R¹ R² R³ R⁴ R⁵ 66 F Me SO₂Me

H 67 F Me SO₂Me

H 68 F Me SO₂Me

H

Example 69 Synthesis of methyl2-[4-(5-fluoro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylphenyl]thiazole-4-carboxylate(Compound 69)

Into 204 mL of dichloromethane was dissolved 11.06 g of Compound 74,followed by dropwise addition of 2.4 mL of bromotrichloromethane at 0°C. over the period of 5 minutes. After 20 minutes of stirring at thesame temperature, 7.6 mL of DBU was added dropwise over the period of 15minutes. After the mixture was stirred at room temperature for 5minutes, the reaction was terminated with 1 mol/L hydrochloric acid. Theorganic layer was separated, washed with water and saturated brine, andthen dried over anhydrous sodium sulfate. The solvent was removed byevaporation under reduced pressure and the resulting residue waspurified by silica gel column chromatography (chloroform) to obtain 9.18g of the title compound as colorless powder.

Melting point: 241-242° C.

¹H-NMR (DMSO-d₆):δ 2.61 (3H,s), 3.38 (3H,s), 3.87 (3H,s), 7.47(1H,ddd,J=2.5,9.0,9.0 Hz), 7.60 (1H,d,J=8.6 Hz), 7.83 (1H,dd,J=2.5,9.9Hz), 8.11 (1H,dd,J=4.7,9.0 Hz), 8.22 (4H,dd,J=2.1,8.6 Hz), 8.44(1H,d,J=2.1 Hz), 8.63 (1H,s).

IR ν_(max)(KBr):3193,3113,3021,3003,2923,1730,1606,1509,1392,1359,1295,1225,1162,1131,988,918cm⁻¹.

Example 70 Synthesis of2-[4-(5-fluoro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylphenyl]thiazole-4-carboxylicAcid (Compound 70)

Into 45 mL of methanol was dissolved 954 mg of Compound 69, and 4.0 mLof 1 mol/L sodium hydroxide was added thereto. After 20 minutes ofstirring under heating and refluxing, the solvent was removed byevaporation under reduced pressure, and the resulting residue wasextracted with ether-water (1/1). To the aqueous layer was added 2 mol/Lhydrochloric acid, and the precipitated crystals were washed with etherto obtain 746 mg of the title compound as colorless powder.

Melting point: 257-258° C.

¹H-NMR (DMSO-d₆):δ 2.59 (3H,s), 3.36 (3H,s), 7.45 (1H,ddd,J=2.3,8.8,8.8Hz), 7.57 (1H,d,J=8.5 Hz), 7.81 (1H,dd,J=2.3,9.9 Hz), 8.09(1H,dd,J=5.0,8.8 Hz), 8.18 (1H,dd,J=2.0,8.5 Hz), 8.42 (1H,d,J=2.0 Hz),8.51 (1H,s).

IR ν_(max)(KBr):3448,3233,3104,3027,2924,1711,1607,1516,1461,1352,1306,1217,1153,1137cm⁻¹.

Example 71 Synthesis of5-fluoro-N-[2-methanesulfonyl-4-(2-methylthiazol-4-yl)phenyl]-3-methylbenzo[b]thiophene-2-sulfonamide(Compound 71)

Into 4.0 mL of chloroform was dissolved 200 mg of Compound 19, and 194mg of benzyltrimethylammonium tribromide was added, followed by 1 hourof stirring at room temperature. The reaction was terminated by addingwater to the reaction solution and then the solvent was once removed byevaporation. The residue was adjusted to pH 2 to 3 by adding 1 mol/Lhydrochloric acid, followed by extraction with ethyl acetate The organiclayer was washed with saturated brine and then dried over anhydroussodium sulfate. The solvent was removed by evaporation under reducedpressure and the resulting residue was washed with methanol to obtain201 mg ofN-(4-bromoacetyl-2-methanesulfonylphenyl)-5-fluoro-3-methylbenzo[b]thiophene-2-sulfonamideas a colorless solid The thus obtainedN-(4-bromoacetyl-2-methanesulfonylphenyl)-5-fluoro-3-methylbenzo[b]thiophene-2-sulfonamide(150 mg) was dissolved into a mixed solution of 1.5 mL of dioxane and1.5 mL of ethanol, and 53 mg of sodium hydrogen carbonate and 26 mg ofthioacetamide were successively added, followed by 2 hours of stirringunder heating and refluxing. The reaction was terminated by adding waterto the reaction solution and then the solvent was removed by evaporationunder reduced pressure. The residue was adjusted to pH 2 to 3 by adding1 mol/L hydrochloric acid, followed by extraction with ethyl acetate.The organic layer was washed with saturated brine and then dried overanhydrous sodium sulfate. The solvent was removed by evaporation underreduced pressure and the resulting residue was purified by silica gelcolumn chromatography to obtain 61 mg of the title compound as lightyellow powder.

Melting point: 217-220° C.

¹H-NMR (CDCl₃):δ 2.68 (3H,s), 2.75 (3H,s), 2.99 (3H,s), 7.27(1H,ddd,J=2.4,8.7,9.0 Hz), 7.33 (1H,s), 7.45 (1H,dd,J=2.4,9.3 Hz), 7.75(1H,dd,J=4.5,9.0 Hz), 7.84 (1H,d,J=8.7 Hz), 8.06 (1H,dd,J=2.1,8.7 Hz),8.35 (1H,d,J=2.1 Hz), 9.55 (1H,s).

IR ν_(max) (KBr):3237,1604,1514,1352,1296,1163,899 cm⁻¹.

Example 72 Synthesis of5-fluoro-N-[2-methanesulfonyl-4-((E)-2-methanesulfinyl-2-methylsulfanylvinyl)phenyl]-3-methylbenzo[b]thiophene-2-sulfonamide(Compound 72)

Under an argon atmosphere, 135 mg of the compound of Reference Example 3was dissolved into 2 mL of THF, and 196 mg of methylmethylsulfinylmethyl sulfide and 862 μL of 40% methanol solution ofTriton B were added successively, followed by 16 hours of stirring underheating and refluxing. After the reaction was terminated by adding 1mol/L hydrochloric acid to the reaction solution, the mixture wasdiluted with ethyl acetate and the solution was washed with water andsaturated brine, successively. After the solution was dried overanhydrous sodium sulfate, the solvent was removed by evaporation underreduced pressure and the resulting residue was purified by silica gelcolumn chromatography (ethyl acetate/hexane=1/1) to obtain 105 mg of thetitle compound as colorless amorphous.

¹H-NMR (CDCl₃):δ2.32 (3H,s), 2.70 (3H,s), 2.76 (3H,s), 3.04 (3H,s), 7.28(1H,ddd,J=2.4,9.0,9.3 Hz), 7.48 (1H,dd,J=2.4,9.3 Hz), 7.52 (1H,s), 7.78(1H,dd,J=4.8,9.0 Hz), 7.83 (1H,d,J=8.7 Hz), 8.02 (1H,dd,J=2.1,8.7 Hz),8.46 (1H,d,J=2.1Hz), 9.65 (1H,s).

IR ν_(max) (KBr):3446,3225,1604,1492,1303,1163,1133,924 cm⁻¹.

The following show instrumental data in each Example.

TABLE 12 Ex- Melting IR am- point (ν cm⁻¹, ple (° C.) H¹-NMR (δ) KBr) 58207-208 CDCl₃ 2.09 (3H, s), 2.69 (3H, s), 3423, 3021, 3.00 (3H, s),3.98(3H, s), 2931, 1658, 7.46(1H, dd, J = 1.9, 8.7 1482, 1351, Hz), 7.73(1H, d, J = 8.7 1296, 1281, Hz), 7.78 (1H, d, J = 1.9 1163, 991, Hz),7.85 (1H, d, J = 8.7 929, 653 Hz), 8.07 (1H, dd, J = 2.1, 8.7 Hz), 8.33(1H, d, J = 2.1 Hz), 9.64 (1H, s). 59 243-245 CDCl₃ 2.13 (3H, s),2.30(3H, s), 3218, 1641, 2.68 (3H, s), 3.01(3H, s), 1495, 1295, 6.83(1H, d, J = 8.7 Hz), 1163, 913 7.27(1H, ddd, J = 2.4, 8.7, 9.0 Hz), 7.46(1H, dd, J = 2.4, 9.0 Hz) , 7.75 (1 H, dd, J= 4.5, 9.0 Hz) , 7.87 (1H,d, J = 8.7 Hz), 8.16 (1H, dd, J = 2.1, 8.7 Hz), 8.42 (1H, d, J = 2.1Hz), 9.66 (1H, s). 60 Amorph- DMSO-d₆ 2.38 (3H, s), 2.59 (3H, s), 3161,3089, ous 3.34 (3H, s), 7.04 (1H, s), 3000, 2912, 7.48 (1H, ddd, J =2.5, 8.9, 1653, 1613, 9.2 Hz), 7.60 (1H, d, J = 1498, 1308, 8.6 Hz),7.84 (1H, dd, J = 1156, 908, 2.5, 9.9 Hz), 8.12 (1H, dd, 647 J = 5.0,8.9 Hz), 8.18 (1H, dd, J = (2.1, 8.6 Hz), 8.36 (1H, d, J = 2.1 Hz). 61176-179 CDCl₃ 1.39 (3H, t, J = 6.9 Hz), 3220, 1660, 2.09 (3H, s), 2.68(3H, s), 1481, 1297, 2.99 (3H, s), 4.22 (2H, q, 1161, 923 J = 2.1 Hz),7.27 (1H, ddd, J = 2.4, 8.7, 9.0 Hz), 7.46 (1H, dd, J = 2.4, 9.0 Hz),7.75 (1H, dd, J = 4.5, 9.0 Hz), 7.86 (1H, d, J = 8.7 Hz), 8.08 (1H, dd,J = 2.1, 8.7 Hz), 8.33 (1H, d, J = 2.1 Hz), 9.66 (1H, s). 62 Amorph-CDCl₃ 2.35 (3H, s), 2.38 (3H, s), 3228, 3060, ous 2.68 (3H, s), 3.01(3H, s), 3023, 2923, 7.27 (1H, ddd, J = 2.4, 8.6, 1606, 1507, 8.8 Hz),7.46 (1H, dd, J = 1442, 1355, 2.4, 9.2 Hz), 7.75 (1H, dd, 1304, 1163, J= 4.7, 8.8 Hz), 7.83 (1H, 1136, 925, d, J = 8.7 Hz), 8.01 (1H, 652 dd, J= 2.1, 8.7 Hz), 8.32 (1H, d, J = 2.1 Hz), 9.61 (1H, s). 66 242-244DMSO-d₆ 2.44 (3H, s), 3.21 (3H, s), 3221, 3132, 4.28 (2H s), 7.31 (1H,ddd, 2927, 1615, J = 2.0, 9.0, 9.0 Hz), 7.46 1520, 1484, (1H, d, J = 8.6Hz), 7.65 1355, 1341, (1H, dd, J = 2.0, 8.0 Hz), 1304, 1100 7.89 (1H,s), 7.95 (1H, dd, J = 4.8, 9.0 Hz), 7.98 (1H, d, J = 8.6 Hz), 8.24 (1H,s). 67 197-199 CDCl₃ 2.69 (3H, s), 3.03 (3H, s), 3228, 2927, 4.53 (2H,s), 7.27 (1H, ddd, 1613, 1560, J = 2.4, 8.6, 8.6 Hz), 7.47 1516, 1484,(1H, dd, J = 2.4, 9.2 Hz), 1440, 1398, 7.70 (1H, s), 7.75 (1H, dd, 1373,1357, J = 4.8, 8.6 Hz), 7.92 (1H, 1304, 1250, d, J = 8.8 Hz), 8.20 (1H,1194, 1162, dd, J = 2.0, 8.8 Hz), 8.49 1099 (1H, d, J = 2.0 Hz), 9.72(1H, s). 68 206-208 CDCl₃ 2.22 (3H, s), 2.69 (3H, s), 3231, 3131, 3.02(3H, s), 7.28 (1H, ddd, 2925, 1614, J = 2.4, 9.0, 9.0 Hz), 7.42 1519,1486, (1H, d, J = 2.0 Hz), 7.46 1439, 1355, (1H, dd, J = 2.4, 9.2 Hz),1332, 1302, 7.75 (1H, dd, J = 4.8, 9.0 1275, 1161, Hz), 7.89 (1H, d, J =8.6 1138, 1099 Hz), 8.17 (1H, dd, J = 2.0, 8.6 Hz), 8.47 (1H, d, J = 2.0Hz), 9.70 (1H, s).

Example 73 Synthesis of5-fluoro-N-[2-methanesulfonyl-4-(oxazol-2-yl)phenyl]-3-methylbenzo[b]thiophene-2-sulfonamide(Compound 73)

Compound 24 (902 mg) was melted over an open fire. The resulting caramellike substance was purified by silica gel column chromatography(chloroform) and then recrystallized (ethyl acetate-hexane) to obtain306 mg of the title compound as light yellow crystals.

Melting point: 207-208° C.

¹H-NMR (CDCl₃):δ 2.69 (3H,s), 3.03 (3H,s), 7.23 (1H,s), 7.27(1H,ddd,J=2.6,8.8,8.8 Hz), 7.46 (1H,dd,J=2.6,9.2 Hz), 7.71 (1H,s), 7.76(1H,d,J=4.8,8.8 Hz), 7.91 (1H,d,J=8.7 Hz), 8.21 (1H,dd,J=2.1,8.7 Hz),8.50 (1H,d,J=2.1 Hz), 9.70 (1H,s).

IR ν_(max)(KBr):3237,3140,3020,2925,1615,1519,1481,1354,1303,1163,1139,912,650cm⁻¹.

Example 74 Synthesis of methyl(4R)-2-[4-(5-fluoro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylphenyl]thiazoline-4-carboxylate(Compound 74)

Into 1500 mL of dichloromethane was dissolved 31.04 g of methyl(2R)-2-[4-(5-fluoro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylphenylcarboxyamido]-3-tritylthiopropionate.After the solution was cooled to 0° C., 19.8 mL ofhexamethylphosphoramide was added and 435 mL of dichloromethane solutionof 12.9 mL of titanium tetrachloride was added dropwise (TetrahedronLetters, 42, 4171 (2001)). After 21 hours of stirring at roomtemperature, the reaction was terminated by adding water. The solventwas removed by evaporation under reduced pressure and the resultingresidue was re-dissolved into ethyl acetate. The solution was washedwith water and saturated brine, successively. After drying overanhydrous sodium sulfate, the solvent was removed by evaporation underreduced pressure and the resulting residue was purified by silica gelcolumn chromatography (chloroform) and then recrystallized fromchloroform-hexane to obtain 11.09 g of the title compound as colorlesspowder.

Melting point: 170-171° C.

¹H-NMR (CDCl₃):δ 2.68 (3H,s), 3.03 (3H,s), 3.66 (1H,dd,J=9.1,11.5 Hz),3.73 (1H,dd,J=9.1,11.5 Hz), 3.82 (3H,s), 5.25 (1H,t,J=9.1 Hz), 7.28(1H,ddd,J=2.5,8.7,8.9 Hz), 7.46 (1H,dd,J=2.5,9.2 Hz), 7.76(1H,dd,J=4.7,8.9Hz), 7.85 (1H,d,J=8.6 Hz), 8.01 (1H,dd,J=2.0,8.6 Hz),8.31 (1H,d,J=2.0 Hz), 9.76 (1H,s).

IR ν_(max)(KBr):3186,3029,3000,2954,2920,1744,1606,1498,1357,1293,1225,1163,1131,989,927cm⁻¹.

Example 755-Fluoro-N-(4-hydroxymethyl-2-methanesulfonylphenyl)-3-methylbenzo[b]thiophene-2-sulfonamide

Into 120 mL of toluene was dissolved 2.08 g of Compound 17. Aftercooling to −30° C., 22.5 mL of 1.01 mol/L toluene solution ofdiisobutylaluminum hydride was added thereto. After 5 hours of stirringat the same temperature, water was added to the reaction solution toterminate the reaction and then the mixture was diluted with ethylacetate, followed by addition of saturated aqueous potassium sodiumtartrate solution and 30 minutes of stirring at room temperature. Themixture was extracted with ethyl acetate and the organic layer waswashed with saturated brine and then dried over anhydrous sodiumsulfate. The solvent was removed by evaporation under reduced pressureand the resulting residue was purified by silica gel columnchromatography (ethyl acetate/hexane=1/1) to obtain 1.38 g of the titlecompound as colorless powder.

Melting point: 120-121° C.

¹H-NMR (CDCl₃):δ 2.68 (3H,s), 2.96 (3H,s), 4.68 (2H,s), 7.26(1H,ddd,J=2.4,8.7,9.0 Hz), 7.46 (1H,dd,J=2.4,9.0 Hz), 7.57(1H,dd,J=1.8,8.4 Hz), 7.75 (1H,dd,J=4.5,8.7 Hz), 7.77 (1H,d,J=8.4 Hz),7.86 (1H,d,J=1.8 Hz), 9.48 (1H,s).

IR ν_(max) (KBr):3504,3221,1608,1497,1347,1296,1150,926 cm⁻¹.

Test Example 1

Measurement of Inhibitory Activity of Simian Chymase or Human Chymase

Simian chymase used was obtained from the heart of rhesus monkey throughpurification in accordance with a human heart chymase purificationmethod (J. Biol. Chem., 265, 22348 (1990)), and human chymase used wasobtained from silkworms infected with baculovirus integrated with a geneencoding human chymase (FEBS. Let., 412, 86 (1997)).

Chymase activity was determined with reference to the method known in aliterature (Miyazaki et al., Kekkan, Vol. 20, p. 207 (1997)). That is,the activity was measured by reacting free His-Leu formed together withAng II with o-phthalaldehyde (hereinafter, abbreviated as OPT) toprepare a fluorescent derivative and determining the amountquantitatively by means of a fluorophotometer.

First, 3.6 μmol of each test compound was weighed in a test tube and wasdissolved into 3 mL of DMSO. The DMSO solution was diluted 1000-foldwith 20 mmol/L Tris-hydrochloric acid buffer solution (pH 8.0)containing 0.01% Triton X-100 and 0.5 mol/L potassium chloride toprepare 1.2×10⁻⁶ mol/L solution, which was successively diluted with thebuffer solution to prepare test sample solutions having concentrationsof 1.2×10⁻⁶ mol/L to 1.2×10⁻⁹ mol/L. To 500 μL of the test samplesolution of each concentration or buffer solution was added 50 μL of anenzyme solution, followed by 10 minutes of pre-incubation at 37° C.Then, 50 μL of 0.1 mmol/L Ang I solution was added to initiate areaction. Human angiotensin I (manufactured by SIGMA) was employed asAng I. The enzyme solution to be used for the reaction was adjusted soas to hydrolyze about 60% of substrate under the conditions, and thereaction wherein a buffer solution containing no enzyme was carried outas a blind test. After 120 minutes of incubation at 37° C., the reactionwas terminated by adding 900 μL of 15% of trichloroacetic acid.Thereafter, the reaction mixture was centrifuged at 4° C. at 3,000 rpmfor 10 minutes and 2 mL of 2 mol/L sodium hydroxide and 1 mL of methanolwere added to 1 mL of the resulting supernatant. Thereto was added 100μL of methanol solution containing 1 mg of N-acetyl-L-cysteine and 1 mgof OPT per 1 mL, whereby a derivatization reaction was initiated. Afterthe reaction mixture was left on standing for exactly 1 hour,fluorescence intensity at fluorescence wavelength of 502 nm underexcitation wavelength of 304 nm was measured. The measurement wasrepeated twice for each sample and blind test. The fluorescenceintensity obtained by subtracting the average value at blind test fromthe average value thereof was determined as chymase activity.

In this regard, an enzymatic reaction using a buffer solution instead ofthe test sample solution was carried out as a control, and inhibitoryratio of chymase activity was determined as percentage by dividing thedifference of subtraction of the activity at the addition of the testcompound from the chymase activity at the control by the chymaseactivity at the control. Based on each inhibitory ratio, theconcentration at which 50% of the activity was inhibited (hereinafter,referred to as IC₅₀ value) was calculated. Table 13 shows IC₅₀ values ofrepresentative compounds.

TABLE 13 Simian chymase Human cymase Compound IC₅₀ value (nmol/L) IC₅₀value (nmol/L) Compound 1 50 203 Compound 2 42 Compound 3 178 Compound 4111 Compound 5 150 Compound 7 185 Compound 8 159 Compound 11 100 271Compound 13 271 Compound 14 278 Compound 17 9 56 Compound 19 20 82Compound 20 39 305 Compound 24 2 37 Compound 25 75 Compound 26 10 150Compound 48 6 45 Compound 52 157 Compound 56 102 Compound 63 20 Compound66 39 Compound 68 101 Compound 70 0.4 7 Compound 72 20 Compound 73 55

Test Example 2

Measurement of Cathepsin G Inhibitory Activity and ChymotrypsinInhibitory Activity

Each activity of cathepsin G or chymotrypsin was measured by determiningthe amount of free p-nitroaniline quantitatively using a syntheticsubstrate that is colorless and yields colored product upon hydrolysis,by means of a spectrophotometer. Chymotrypsin Type I-S derived frombovine pancreas was purchased from SIGMA. As cathepsin G, the product ofElastin Products Company, Inc. derived from human purulent sputum wasused. Suc-Ala-Ala-Pro-Phe-pNA (manufactured by SIGMA) was used as thesynthetic substrate. An inhibitory effect of a compound on each enzymewas determined by the following method.

Each test compound (5 μmol) was weighed in a test tube and dissolvedinto 2 mL of DMSO. The DMSO solution was diluted 100-fold with 20 mmol/LTris-hydrochloric acid buffer solution (pH 7.5) containing 0.01% TritonX-100 and 0.5 mol/L potassium chloride to prepare 2.5×10⁻⁵ mol/Lsolution, which was successively diluted to prepare test samplesolutions having concentrations of 2.5×10⁻⁵ mol/L to 2.5×10⁻⁹ mol/L. To200 μL of each test sample solution or buffer solution was added 100 μLof an enzyme solution of 40 μg/mL chymotrypsin or 8 units/mL cathepsinG, followed by 10 minutes of pre-incubation at 37° C. Then, 200 μL of 1mmol/L substrate solution was added to initiate en enzymatic reactionunder a temperature of 37° C. A reaction wherein a buffer solutioncontaining no enzyme was carried out as a blind test, and incubationtime was 30 minutes and 60 minutes for chymotrypsin and cathepsin G,respectively. After the incubation, the reaction was terminated byadding 300 μL of 50% acetic acid, and absorbance at 405 nm was measured.The measurement was repeated twice for each sample and blind test. Theabsorbance obtained by subtracting the average value at blind test fromthe average value of each sample was determined as activity of eachenzyme.

In this regard, an enzymatic reaction using a buffer solution instead ofthe test sample solution was carried out as a control, and inhibitoryratio of each enzyme activity was determined as percentage by dividingthe difference from the subtraction of the activity at the addition ofthe test compound from the enzyme activity at the control by the enzymeactivity at the control. Based on each inhibitory ratio, IC₅₀ value wascalculated.

Table 14 shows IC₅₀ values of inhibitory activities of therepresentative Compounds against Cathepsin Grand Chymotrypsin.

TABLE 14 Inhibitory specificity of active compounds IC₅₀ value (nmol/L)Compound Chymotrypsin Cathepsin G Chymostatin 9.67 5.99 Compound1 >10000 >10000 Compound 4 >10000 >10000 Compound 5 >1000 >1000 Compound7 >1000 >1000 Compound 8 >10000 >10000 Compound 14 >10000 >10000Compound 17 >10000 >10000 Compound 24 >10000 >10000 Compound26 >10000 >10000 Compound 48 >10000 >10000 Compound 70 >10000 >10000

Test Example 3

Stability in Rat Plasma

Stability of the compounds of the invention in rat plasma wasinvestigated.

Male SD rats (7-week-old) were anesthetized with ether under over-nightfasting conditions and, after an abdominal part was incised, blood wascollected from aorta abdominalis using a heparinized disposable plasticsyringe. The blood was centrifuged under cooling to collect asupernatant plasma. The collected plasma was stored under freezing at−30° C. and was melted before use. After a test compound was dissolvedin DMSO, the solution was added to 200 μL of the plasma so as to be 10μg/mL, followed by incubation at 37° C. After 60 minutes, the mixturewas acidified by adding 200 μL of 0.1 mol/L hydrochloric acid, and thenextracted twice with 2 mL of ethyl acetate. The resulting organic layerwas evaporated to dryness under a nitrogen gas flow and the residue wasdissolved into 200 μL of acetonitrile to prepare a sample solution. Onthe other hand, the test compound was dissolved into 1% acetonitrilesolution of DMSO so as to be 10 μg/mL as a control solution. The samplesolution and control solution was investigated by high performanceliquid chromatography (hereinafter, abbreviated as HPLC). Residual ratio(%) was determined as percentage by dividing the peak area of the samplesolution by the peak area of the control solution.

HPLC Conditions:

Column: Waters Nova Pack C₁₈ (inner diameter: 3.9 mm, length: 150 mm)

Mobile phase A: acetonitrile/water=10/90

Mobile phase B: acetonitrile/methanol=50/50

Eluent: Mobile phase A-mobile phase B (100/0 to 0/100, linear gradient,50 minutes)

Flow rate: 1.0 mL/minute

Amount of injection: 50 μL

Table 15 shows residual ratios of representative compounds in ratplasma.

TABLE 15 Compound Residual ratio in rat plasma (%) Compound 1 93.9Compound 4 93.5 Compound 5 85.2 Compound 7 96.4 Compound 8 92.0 Compound14 79.2 Compound 19 96.2 Compound 24 100 Compound 26 100

Test Example 4

Test in Rat Monocrotaline-Induced Pulmonary Hypertension Model

Into 1.2 mL of 1 mol/L hydrochloric acid was dissolved 200 mg ofmonocrotaline, followed by addition of 5 mL of distilled water. Thesolution was neutralized with 0.5 mol/L sodium hydroxide, and furtherdiluted with distilled water so as to be 10 mL (20 mg/mL). Moreover, asolution containing the solvent alone without monocrotaline was preparedas Solvent A. A test compound was suspended into olive oil (25 mg/mL).Furthermore, a solution containing no test compound but the solventalone was prepared as Solvent B.

Monocrotaline (60 mg/kg-body weight) was administrated subcutaneously atthe posterior region of neck of five 5-week-old SD male rats. From 3days before monocrotaline administration to 20 days after theadministration, a test compound was administered intraperitoneally twicea day at a dose of 50 mg/kg-body weight. On the next day of the finaladministration of the test compound, the rats were fixed supinely underanesthetization with intraperitoneal administration of sodiumpentobarbital. And then blood pressure was measured with cannulainserted from left carotid artery and systolic pressure at rightventricle was measured with cannula inserted from right carotid arteryand introduced into-right ventricle, via a pressure transducer by meansof a pressure-strain gauge. After slaughter of the animals, the heartwas removed and weight of right ventricle, weight of left ventricle andseptum, and diameter and medial thickness of pulmonary artery having adiameter within a range of 50 to 150 μm were measured. Moreover, fromthese measured values, a weight ratio of right ventricle/(leftventricle+septum) and medial thickening ratio {(medial thickness/outerdiameter of the blood vessel)×100} were determined. In this regard, agroup wherein the rats to which monocrotaline was administered wastreated with Solvent B alone in an amount of 2 mL/kg-body weight in thesame administration schedule as above was named “Solvent-administeredgroup”. In addition, a group wherein the rats to which Solvent A wasadministered in an amount of 3 mL/kg-body weight was treated withSolvent B in an amount of 2 mL/kg-body weight was named“Monocrotaline-untreated group”. The results are shown in Table 16.

TABLE 16 Monocrotaline-treated group Monocrotaline- Solvent- Testcompound untreated administered group group group (Compound 17) Numberof rats 5 4 to 5 3 to 4 Average blood 105 ± 11  85 ± 6  111 ± 19 pressure (mmHg) Systolic pressure at 29 ± 2  63 ± 15 57 ± 11 rightventricle Weight of right 154 ± 7  246 ± 30  233 ± 24  ventricle (mg)Weight ratio of right 0.24 ± 0.00 0.44 ± 0.05 0.39 ± 0.04 ventricle/(left ventricle + septum) Medial 7.16 ± 0.58 14.28 ± 2.13  10.55 ± 1.80 thickening ratio

In the group to which a test compound (Compound 17) was administered,thickening of medial muscular layer (increase of medial thickeningratio) appearing as a result of progress of pulmonary hypertension wassuppressed. Since the test compound exhibited a tendency of suppressingthe thickening of medial muscular layer and of suppressing the increaseof weight of right ventricle without lowering systemic blood pressure inmonocrotaline-induced pulmonary hypertension model, it was confirmedthat the compound of the invention was effective for preventing andtreating pulmonary hypertension.

Test Example 5

Investigation in Hamster Adhesion Model

Five-week-old female hamster (10 hamsters per each group) wasanesthetized by administering intraperitoneally pentobarbital sodium (50mg/kg) and, after midline incision at abdominal region, the uterus wasrubbed with a cotton swab. Thereafter, 1 mL of saline solution of a testcompound (Compound 24: 10⁻⁴ mol/L) was added dropwise intraperitoneally,and then the incised part was sutured. On the other hand, as a control,saline alone was added dropwise, followed by a similar treatment.

After 4 weeks from the operation, the animals were slaughtered, theabdominal part was exposed and adhesion was investigated. The adhesionwas judged using the following 5-grade scoring system and the data wereanalyzed according to Mann-Whitney U test.

Adhesion Score

-   -   0: No adhesion    -   1: Very weak adhesion (film-like adhesion easily releasable)    -   2: Limited adhesion (strong adhesion difficult to release at        only one point)    -   3: Wide-range adhesion (strong adhesion difficult to release at        several points)    -   4: Very strong adhesion (very strong adhesion impossible to        release)

As a result, average score of the control group was 2.0, while averagescore of the group to which a test compound (Compound 24) wasadministered was 0.9. Thus, postoperative adhesion was significantlysuppressed (p<0.05).

Test Example 6

Investigation in Rat Cecum-Scraped Adhesion Model

Six-week-old SD rats were subjected to midline incision at lowerabdominal region under pentobarbital anesthetization (70 mg/kg,intramuscular injection), and the cecum was taken out of the incisedpart. Two parts of serous membrane of the cecum (about 2 cm² each) wererubbed with a cotton swab a hundred times until petechial hemorrhageoccurs, followed by dropwise addition of 100 μL of ethanol. The cecumwas again set in abdominal cavity, and then, 2 mL of a phosphatebuffered saline (hereinafter, abbreviated as PBS, pH 7.4) solution of atest compound (Compound 24 or 70) was added dropwise intraperitoneally,and then the incised part was sutured. The concentration of each testcompound solution was 10⁻⁵ mol/L in a control group, PBS alone was addeddropwise, followed by a similar treatment. Each group had 11 or 12 rats.After 1-week from the operation, the animals were slaughtered, theabdominal part was re-incised and an adhesion state of the cecum wasevaluated according to adhesion scores using the adhesion intensity andadhesion area as indexes. The score values were determined according tothe following 5-grade scores. In this connection, adhered region (%) wasdetermined as percentage of total area of the adhered parts relative tothe area of the rubbed regions.

Adhesion Score

-   -   0: No adhesion    -   1: Easily releasable adhesion limited to only a part (less than        25% of adhered region)    -   2: Easily releasable adhesion over a wide range (25% or more of        adhered region) or limited adhesion to only a part (less than        25% of adhered region) difficult to release    -   3: Wide-range adhesion (25% or more of adhered region) difficult        to release    -   4: Adhesion impossible to release or adhesion accompanied by        serous membrane injury at release

As a result, with regard to adhesion score distribution, totalpercentage of scores 3 and 4 showing severe adhesions was 63.6% in thecontrol group, while the percentage decreased to 41.7% and 33.3% in theadministered groups of administering 10⁻⁵ mol/L solution of Compound 24and Compound 7, respectively. Thus, adhesion was suppressed byadministering the compounds.

Test Example 7

Investigation in Canine Eye Postoperative Adhesion Model

A beagle dog was anesthetized and each conjunctiva of both eyes thereofwas peeled in a size of 10 mm×5 mm under a stereomicroscope. At thattime, Tenon was left at conjunctival side and was not left at scleralside. After a sponge immersed in a saline solution of a test compound(Compound 70) was placed at the incised part for 3 minutes, the incisedpart was put in one stitch with 10-0 nylon thread. The concentration ofthe test compound solution was 10⁻⁴ mol/L and a saline was used in acontrol group (6 dogs per each group).

After 7 days from the operation, the animals were slaughtered, theeyeballs were taken out and adhesion was investigated. After the threadused at the stitching in the model preparation was cut, evaluation wascarried out by pulling the conjunctiva part with tweezers and scoringthe adhesion state. The score values were determined according to thefollowing 5-grade scores, and Mann-Whitney U test was used for analyzingthe data.

Adhesion Score

-   -   0: No adhesion    -   1: Very weak adhesion (film-like adhesion easily releasable)    -   2: Limited adhesion (strong adhesion difficult to release at        only one point)    -   3: Wide-range adhesion (strong adhesion difficult to release at        several points)    -   4: Very strong adhesion (very strong adhesion impossible to        release)

As a result, average score of the control group was 3.67, while averagescore of the test compound (Compound 70) group was 2.67. Thus,postoperative adhesion was significantly suppressed (p<0.05).

Formulation Example 1

Manufacture of Tablets

Tablets having 200 mg weight and containing 5 mg of Compound 24 pertablet were manufactured by mixing 5 g of Compound 24, 125 g of lactose,40 g of corn starch and 20 g of crystalline cellulose, adding 10%ethanol solution of 6 g of hydroxypropyl cellulose, kneading andgranulating the mixture, preparing granules by extrusion through ascreen having a mesh size of 8 mm, adding 4 g of magnesium stearateafter drying the granules, and subjecting the mixture to compressionmolding.

Formulation Example 2

Manufacture of Injections or Liquids

After 50 mg of Compound 24 and 900 mg of sodium chloride were dissolvedin 90 mL of water for injection, the solution was adjusted to pH 7 with0.1 mmol/L-sodium hydroxide and total amount was made 100 mL using waterfor injection. Then, the solution was aseptically filtered, and 2 mL ofthe filtrate was charged into each glass ampoule to manufactureinjections or liquids containing 1 mg of Compound 24 per ampoule.

Formulation Example 3

Manufacture of Suppositories

Witepsol H-15 was heated to melt and Compound 24 was added so as to be10 mg/mL, followed by homogeneous mixing. Two mL of this mixture wasinjected into each plastic container for suppository and cooled tomanufacture suppositories containing 20 mg of Compound 24 persuppository.

Formulation Example 4

Manufacture of Eye-Drops

Into 80 mL of purified water were dissolved 50 mg of Compound 24, 0.1 gof sodium dihydrogen phosphate dihydrate, 0.9 g of sodium chloride and 5mg of benzalkonium chloride, and 0.1 mol/L aqueous sodium hydroxidesolution was added to adjust the solution to pH 7, followed by addingpurified water to make total volume 100 mL. After the solution wasaseptically filtered, 5 ml of the filtrate was charged into eachpolypropylene container for eye-drops to manufacture 0.05% eye-drops ofCompound 24.

Formulation Example 5

Manufacture of Aerosol

After 100 mg of Compound 17 was suspended into 10 g of ethanol, 3 g ofthe liquid was charged into a pressure-resistant aluminum container, andthen the valve part was firmly fixed. Into the container was charged 4.2g of 1,1,1,2-tetrafluoroethane to form an aerosol.

INDUSTRIAL APPLICABILITY

The N-substituted benzothiophenesulfonamide derivatives orpharmaceutically acceptable salts thereof of the invention have aselective inhibitory action on chymase and are useful as agents forpreventing or treating cardiac and circulatory diseases, especiallycardiac infarction, restenosis after PTCA and intimal thickening afterbypass grafting, pulmonary hypertension caused by abnormal increase ofproduction of angiotensin II or endothelin I based on chymase activity,or by activation of mast cell, and are useful as agents for preventingadhesion after surgery.

1. An N-substituted beozothiophenesulfonamide derivative represented byformula (I):

wherein R¹ represents a hydrogen atom, a halogen atom or a lower alkylgroup; R² represents a lower alkyl group; R³ and R⁴ each may be the sameor different and represents a hydrogen atom, a lower alkoxycarbonylgroup, a lower alkylsulfonyl group, a benzoyl group, an acyl grouphaving 1 to 4 carbon atoms, a lower alkoxy group, a loweralkoxycarbonylmethylthioacetyl group, a nitro group, —CONHR⁶ in which R⁶represents a hydrogen atom, a lower alkoxycarbonylmethyl group, acarboxymethyl group or —CH(CH₂OH)COOR⁷ in which R⁷ represents a hydrogenatom or a lower alkyl group, a hydroxy lower alkyl group, or a cyanogroup, provided that R³ and R⁴ are not hydrogen atoms at the same time;and R⁵ represents a hydrogen atom, a lower alkoxy group or a lower alkylgroup, except the compounds represented by formulae:

or a pharmaceutically acceptable salt thereof.
 2. The N-substitutedbenzothiophenesulfonamide derivative according to claim 1, wherein saidderivative or a pharmaceutically acceptable salt thereof is selectedfrom the group consisting of methyl4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylbenzoate,sodium methyl4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylbenzoate,isopropyl4-(5-chloro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylbenzoate,N-(4-acetyl-2-methanesulfonylphenyl)-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,N-(4-benzoyl-2-methanesulfonylphenyl)-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide,methyl4-(5-fluoro-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylbenzoate,methyl4-(5-methyl-3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylbenzoate,N-(4-acetyl-2-methanesulfonylphenyl)-5-fluoro-3-methylbenzo[b]thiophene-2-sulfonamide,methyl4-(3-methylbenzo[b]thiophene-2-sulfonylamino)-3-methanesulfonylbenzoate,and5-fluoro-N-[2-methanesulfonyl-4-((E)-2-methanesulfinyl-2-methylsulfanylvinyl)phenyl]-3-methylbenzo[b]thiophene-2-sulfonamide.3. A pharmaceutical composition comprising an N-substitutedbenzothiophenesulfonamide derivative represented by formula (I):

wherein R¹ represents a hydrogen atom, a halogen atom or a lower alkylgroup; R² represents a lower alkyl group; R³ and R⁴ each may be the sameor different and represents a hydrogen atom, a lower alkoxycarbonylgroup, a lower alkylsulfonyl group, a benzoyl group, an acyl grouphaving 1 to 4 carbon atoms, a lower alkoxy group, a loweralkoxycarbonylmethylthioacetyl group, a nitro group, —CONHR⁶ in which R⁶represents a hydrogen atom, a lower alkoxycarbonylmethyl group, acarboxymethyl group or —CH(CH₂OH)COOR⁷ in which R⁷ represents a hydrogenatom or a lower alkyl group, a hydroxy lower alkyl group, or a cyanogroup, provided that R³ and R⁴ are not hydrogen atoms at the same time;and R⁵ represents a hydrogen atom, a lower alkoxy group or a lower alkylgroup, or a pharmaceutically acceptable salt thereof.
 4. A chymaseinhibitor comprising the pharmaceutical composition of claim
 3. 5. Anagent for treating hypertension, hypercardia, cardiac failure, cardiacinfarction, arteriosclerosis, diabetic or non-diabetic renal disease,diabetic retinopathy, ischemic re-perfusion disorder, restenosis afterpercutaneous transluminal coronary angioplasty, intimal thickening afterbypass grafting, chronic rheumatism, keloid, psoriasis, allergy,inflammation, asthma, atopic dermatitis, or pulmonary hypertension,wherein the agent comprises the pharmaceutical composition of claim 3.6. An agent for preventing postoperative tissue adhesion in a patient inneed thereof comprising the pharmaceutical composition of claim 3.